Anthoula Lazaris - Academia.edu (original) (raw)

Papers by Anthoula Lazaris

Research paper thumbnail of Predictive Biomarker Profiles in Cancer Using a Unique AI Model Based on Set Theory

The current study applies a new artificial intelligence (AI) method, ALiX, which is based on inte... more The current study applies a new artificial intelligence (AI) method, ALiX, which is based on interval arithmetic, to analyze and interpret biological data for a clinical problem: identification of biomarkers for cancer diagnosis. Key unique and important features of this study is that ALiX provides an explanation to our medical hypothesis in the form of a list of ranked protein biomarkers that identifies which biomarkers are the most significant drivers of the predicted outcome, a capability that is not currently available in other AI applications. This study identifies a unique profile for stratifying cancer patients and for further stratifying the patients with cancer into subtypes that respond to treatment or not.

Research paper thumbnail of Transforming Growth Factor-Beta 1 Induces Neutrophil Apoptosis in Colorectal Cancer Liver Metastases

Vessel co-option correlates with resistance against anti-angiogenic agents and chemotherapy in co... more Vessel co-option correlates with resistance against anti-angiogenic agents and chemotherapy in colorectal cancer liver metastasis (CRCLM). We previously identified higher intensity of neutrophils in the tumour microenvironment of vessel co-opting CRCLM lesions compared to their angiogenic counterparts. Herein, we demonstrated that over 50% of the neutrophils in vessel co-opting lesions are expressing pro-apoptotic markers including cleaved caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1). Our previous publications suggested upregulation of transforming growth factor-beta (TGFβ1) in the microenvironment of vessel co-option CRCLM. Therefore, we examined the effect of TGFβ1 on the expression of cleaved caspase-3 and PARP-1 in neutrophils in vitro. Significantly, we noticed the upregulation of pro-apoptotic markers upon exposure to TGFβ1. This finding might pave the way to determine the role of neutrophils in developing vessel co-option in CRCLM in the future.

Research paper thumbnail of Targeting Liver Metastases to Potentiate Immunotherapy In MS-stable colorectal cancer- A Scoping Review of Literature

While Immunotherapy has revolutionized the treatment of several cancers such as lung cancer, mela... more While Immunotherapy has revolutionized the treatment of several cancers such as lung cancer, melanoma, and other cancers, most colorectal cancer patients remain resistant. This resistance to immunotherapy may partially stem from the fact that colorectal cancer very commonly metastasizes to the liver. The liver is known to play an immunotolerant role in in other contexts such as organ transplantation, viral disease, and autoimmune disease. Recent studies reveal the mechanisms in which liver metastases restrict the efficacy of immunotherapy. This effect was shown to be reversable in colorectal cancer mice models, when colorectal liver metastases were irradiated. It is possible that targeting liver metastases with locoregional therapies such as ablation, resection or irradiation may reverse the immunosuppressive effect of liver microenvironment and potentiate immunotherapy systemically. During the past decade, several clinical trials are trying to extrapolate the results achieved in an...

Research paper thumbnail of A single center survival analysis of patients with colorectal cancer who underwent next generation sequencing

Journal of Clinical Oncology

31 Background: Colorectal cancer (CRC) remains a lethal diagnosis with an overall 5-year survival... more 31 Background: Colorectal cancer (CRC) remains a lethal diagnosis with an overall 5-year survival rate of 5-10% for patients with unresectable metastatic disease. The advent of next generation sequencing allows tailored systemic therapy to specific mutations with the goal of improving patient survival. McGill University Health Center instituted next generation sequencing in 2019. Our study aims to evaluate survival outcomes in patients who underwent NGS testing. Methods: A retrospective collection of data on all patients with CRC who were presented at both lower gastroenterology and hepatobiliary tumor boards from January 2019 through July 2022 ( n= 498). Survival and was compared between patients who were found to have genetic alterations identified using the Illumina Miseo platform. Statistical Analysis was performed with GraphPad Prism. Results: A total of 321 (64%) patients had NGS performed on either their primary tumor or a metastasis. A total of 229 (71%) CRC patients had gen...

Research paper thumbnail of Extended criteria liver resection: Can noncurative intent resection of colorectal liver metastasis improve survival?

Journal of Clinical Oncology

164 Background: From initially believed to be a palliative diagnosis, CRLM management has ranged ... more 164 Background: From initially believed to be a palliative diagnosis, CRLM management has ranged from nonoperative, resection of only solitary lesions, resection only if 1 cm margin could be obtained, to major hepatectomies with liver regenerative procedures. With a greater understanding of the disease and advances in systemic therapy, clinicians have been able to continuously push the envelope in both resection and local therapies to improve overall survival in patients with CRLM. The constant evolution of management for CRLM raises the question – would patients benefit from a non-curative intent resection by decreasing overall tumor burden? Is there a role for debulking of disease as an extended criterion to improve median survival? Methods: A retrospective study was conducted by identifying patients who consented to participate in the liver disease biobank research program. Consented patients with CRLM evaluated for a two-stage hepatectomy (TSH) between 2012-2020 were identified....

Research paper thumbnail of Histopathological growth patterns determines the outcomes of colorectal cancer liver metastasis that have undergone liver resection

Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis with an overa... more Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis with an overall 5-year survival rate of 5–10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly differing rates of patients survival, and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden and pattern of cancer progression in light of their HGP’s, and to consider their potential effect on surgical decision making. Methods We performed a retrospective multivariate analysis on clinical data from patients with CRCLM (n = 275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring. Results 109 patients (42.2%) were classified as desmoplastic and angiogenic whereas 149 patients (...

Research paper thumbnail of Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1 signaling pathway attenuates vessel co-option in colorectal cancer liver metastases

Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs... more Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs) including angiogenic desmoplastic HGP (DHGP) and non-angiogenic replacement HGP (RHGP). The RHGP lesions obtain their blood supply through vessel co-option, where the cancer cells hijack the pre-existing blood vessels of the surrounding liver tissue. Consequently, anti-angiogenic therapies are less efficacious in CRCLM patients with RHGP lesions. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) and the development of vessel co-opted CRCLM lesions in vivo. However, the mechanisms underlying Ang1 upregulation in vessel co-opting CRCLM lesions are unclear. Herein, we demonstrated that transforming growth factor β1 (TGFβ1) modulates the expression of Ang1 in hepatocytes in vitro. Significantly, pharmaceutical inhibition of integrin alpha-5/beta-1 (ITGα5β1) through ATN-161 impaired TGFβ1-dependent Ang1 expression in vitro and in vivo. Moreover, b...

Research paper thumbnail of The molecular mechanisms underlying neutrophil infiltration in vessel co-opting colorectal cancer liver metastases

Frontiers in Oncology

Colorectal cancer liver metastases (CRCLMs) have two major histopathological growth patterns (HGP... more Colorectal cancer liver metastases (CRCLMs) have two major histopathological growth patterns (HGPs): desmoplastic (DHGP) and replacement (RHGP). The DHGP tumours derive their vasculature by angiogenesis, while the RHGP tumours use vessel co-option. Various studies have associated RHGP tumours with an unfavourable prognosis, as well as high levels of resistance to anti-angiogenic agents and chemotherapy. Recently, we reported higher numbers of neutrophils in the tumour microenvironment (TME) of vessel co-opting tumours compared to their angiogenic counterparts. However, the molecular mechanisms underlying this phenotype are unclear. Herein, we suggested a positive correlation between the expression of angiopoietin-1 (Ang1) in the hepatocytes and the presence of neutrophils in vessel co-opting tumours. Importantly, upregulation of Ang1 in the hepatocytes is associated with the presence of runt-related transcription factor-1 (RUNX1) in the neighboring cancer cells in vitro and in vivo....

Research paper thumbnail of Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Research paper thumbnail of Volumetric Based Quantification of Histopathological Growth Patterns Is Most Predictive of Progression Free Survival Following Resection of Colorectal Liver Metastases

Research paper thumbnail of Eliciting a Systemic Immune Response against Liver Tumors Utilizing Locoregional Therapies - A Systematic Review of Prospective Studies

Research paper thumbnail of Abstract 1580: Cancer cells promote phenotypic alterations in adjacent hepatocytes to facilitate vessel co-option in colorectal cancer liver metastasis

Cancer Research

Vessel co-option is associated with resistance against anti-angiogenic therapy in colorectal canc... more Vessel co-option is associated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opted lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding non-malignant tissue and hijack them to gain access to nutrient. In order to access the sinusoidal vessels, the cancer cells must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, motility, epithelial-mesenchymal transition (EMT) and autophagy pathways in hepatocyte’s displacement by cancer cells. We demonstrated that cancer cells induce the expression of the proteins that associated with upregulation of apoptosis, motility and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observed upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and Actin Related Prote...

Research paper thumbnail of Abstract 5291: Characterizing the interplay between angiogenic and immunoactive factors of hepatocellular carcinoma

Cancer Research

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death globally. Pati... more Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death globally. Patients typically present at an advanced stage and less than 50% reach the maximum 1-year survival rate, when given as first-line treatment, Sorafenib. This highlights the need for early detection and novel therapeutic targets crucial to increase overall survival (OS) for patients with HCC. Given the important role of angiogenesis in HCC from its early stage and its rich immune composition, anti-angiogenic and immune checkpoint inhibitors (ICI), are two therapeutic approaches when combined marked the first treatment in more than a decade to significantly improve the overall survival and progression-free survival in patients with advanced HCC compared to Sorafenib. While the combination of agents inhibiting angiogenesis and ICI have recently entered the clinic, the interplay between angiogenic factors and immunity in the context of this approach remains poorly understood. Here we focus on un...

Research paper thumbnail of Abstract 6154: Distinct immunosuppressive environments elicited in vessel co-opting and angiogenic colorectal cancer liver metastases and changes following treatment

Cancer Research

Colorectal cancer (CRC) is the third most common cancer worldwide and 50% of CRC patients develop... more Colorectal cancer (CRC) is the third most common cancer worldwide and 50% of CRC patients develop liver metastases. Colorectal cancer liver metastases (CRCLM) present as two major histological growth patterns (HGP) that predict response to treatment/survival: 1. angiogenic tumors characterized by a desmoplastic stroma separating CRC cells from the liver parenchyma and are highly angiogenic and 2. co-opting tumors where tumor cells infiltrate the parenchymal cells in the liver and grow by co-opting the sinusoidal blood vessels between the liver cell plates without sprouting angiogenesis. Angiogenic tumors receiving neoadjuvant anti-angiogenics (anti-VEGF) and chemotherapy have more than double the 5-year overall survival compared to patients with co-opting tumors who have received the same neoadjuvant regimen. In addition, our clinical data revealed that anti-angiogenics could negatively affect outcomes in patients with co-opting lesions. The goal of our study is to understand how th...

Research paper thumbnail of Loss of ATAD3A contributes to NAFLD through the accumulation of lipids and damaged mitochondria

Research paper thumbnail of Results from consensus-oriented decision-making process (CODM) for a primary care based biobank: The quebec experience

Population health and epidemiology

Fundamental research at the primary care level is needed. Medical research has been mostly hospit... more Fundamental research at the primary care level is needed. Medical research has been mostly hospitalbased and focused on molecular mechanisms. There is frequently a discordance between primary care based questions and hospital care-based answers. Biobanks, or biorepositories, designed to provide high quality biospecimens and associated data for disease specific research or population studies, have sparked numerous discussions amongst researchers, scientists, policymakers, ethicists, lawyers and even patient advocate groups. In the era of translational research, there has been an increase of biobanks due to higher demand of biospecimens and data enabling translational research. Therefore, the generation of evidence at the primary care level requires substantial networks of primary care practitioners and investigators in the development of a primary care biobank. While there are numerous online resources and courses available to setup a biobank, there is little information available on the "how-to" for integration within an institution or a network. Each biobank's procedures and plans may be particular to a region or an institution, and the "how-to" may likewise differ. The method(s) used around the numerous meetings and discussions amongst experts to initiate a biobank project is not well described or defined in the literature. The purpose of this paper is to explore the cohesion level of different foundational capabilities identified in a biobank framework using the consensus-oriented decision-making (CODM) process in order to provide guidance in the development of a primary care biobank framework. This study is based on a consensus-based theory. A total of six foundational capabilities were discussed and consensus on cohesions was obtained for each capability. With a number of these capabilities, consensus was achieved, after thematic analysis of the transcript and coding of 120 relevant texts, a number of themes were identified. The involvement of participants at the governance of the biobank, the inclusion of participants in the strategy and mission of the primary care based biobank, as well as ensuring the balance of power for inclusive participation of centres in the biobank are some of the descriptive themes identified during cohesion consensus throughout the foundational capabilities. Determining cohesion levels to develop policies and guidelines is an added tool in the development of a biobank as well as facilitating a "successful" implementation

Research paper thumbnail of Abstract A26: Immune profiling and organoids generation of a rare case of prostate cancer liver metastasis

Cancer Immunology Research, 2020

Introduction: Prostate cancer (PCa) is the second most frequent cancer in men and a leading cause... more Introduction: Prostate cancer (PCa) is the second most frequent cancer in men and a leading cause of cancer-related mortality. Despite major advances in immunotherapy, PCa remains a poor responder. Metastatic PCa is responsible for the majority of PCa-associated mortality. Most PCa metastases are multifocal and display a strong bones tropism (91.1% of cases), but PCa metastases can also spread to the lymph nodes (8.7%), lungs (5.7%), liver (4.5%) and brain (1.8%). Liver metastases are associated with worse prognosis but due to their multifocal nature and frequent spreading to other sites, PCa metastases are rarely resected. Therefore, immunologic characterization of these lesions concomitant with generation of research tools derived from these lesions are urgently needed to understand how to intercept disease progression. Methods: A 62-year-old male who previously underwent radical prostatectomy in 2016 was diagnosed in July 2018 with a single liver metastasis (5.3 cm) by MRI. The t...

Research paper thumbnail of Abstract 2834: Metastatic colorectal cancer: characterization of distinct histological growth patterns which demonstrate different response to current treatment regimes

Cancer Research, 2017

Colorectal cancer (CRC) is the third most common cancer in North America, and the third leading c... more Colorectal cancer (CRC) is the third most common cancer in North America, and the third leading cause of cancer-related death. About 50% of patients will be diagnosed with CRC liver metastasis (CRCLM) during the course of their disease. We have identified two major histological growth patterns (HGP) in CRCLM resected from patients. In the desmoplastic HGP (DHGP), the tumor cells are enclosed within a desmoplastic stromal ring, physically separating them from the normal liver tissue. In the replacement HGP (RHGP), the tumor cells replace normal hepatocytes without disrupting adjacent cells or structures within the liver parenchyma. We have recently shown that patients with RHGP lesions who received neoadjuvant bevacizumab plus chemotherapy had a worse pathological response and five-year overall survival. Our group has also shown that RHGP CRCLM is resistant to anti-angiogenic therapy due to it promoting vessel co-option as a means of tumor vascularization, rather than VEGF-dependent ...

Research paper thumbnail of Abstract 1695: Vascularization of colorectal cancer liver metastasis: correlation with growth patterns

Cancer Research, 2016

Colorectal cancer (CRC) is the third leading cause of cancer-related death in North America. Appr... more Colorectal cancer (CRC) is the third leading cause of cancer-related death in North America. Approximately 50% of patients will be diagnosed with CRC liver metastasis (CRLM) during the course of their disease. Untreated, patients will survive for only a few months, but with chemotherapy, a median survival of 20 months can be achieved. At present, no reliable indicators exist to predict outcome or prognosis in treatable patients. Moreover, no biological parameters are currently being considered for patient stratification into different treatment groups. We examined CRCLM resected from patients and have identified two major histologic growth patterns (HGP): a desmoplastic (DHGP) pattern and a replacement (RHGP) pattern where tumor cells replace parenchymal cells in the liver plates. These HGP involve distinct modes of angiogenesis and host cell responses. Namely, liver metastases with a RHGP grow by co-opting the stroma, without hypoxia-induced angiogenesis and with little perturbatio...

Research paper thumbnail of Eukaryotic Translation Initiation Factor 4E–Induced Progression of Primary Human Mammary Epithelial Cells along the Cancer Pathway Is Associated with Targeted Translational Deregulation of Oncogenic Drivers and Inhibitors

Cancer Research, 2007

Pathologic redirection of translational control by constitutive activation of eukaryotic translat... more Pathologic redirection of translational control by constitutive activation of eukaryotic translation initiation factor 4F (eIF4F), the cap-dependent translation initiation apparatus, is an obligatory step in oncogenesis; however, its mechanism remains undefined. Here, we simulate this pro-oncogenic state by overexpressing eIF4E, the rate-limiting component of eIF4F, in primary human mammary epithelial cells (HMECs) and examine the resultant changes in cell biology and gene expression profiles of total and polyribosome-bound mRNA genome wide. Overexpressed eIF4E rescues primary HMECs from telomere-independent growth arrest and disables checkpoints governing S-phase entry as well as apoptosis in HMECs immortalized by telomerase, imparting cells with proliferative and survival autonomy. Although the transcriptional response to increased eIF4E was modest, the translational response was large, selective, and bidirectional. In addition to translational activation of known and novel eIF4E-...

Research paper thumbnail of Predictive Biomarker Profiles in Cancer Using a Unique AI Model Based on Set Theory

The current study applies a new artificial intelligence (AI) method, ALiX, which is based on inte... more The current study applies a new artificial intelligence (AI) method, ALiX, which is based on interval arithmetic, to analyze and interpret biological data for a clinical problem: identification of biomarkers for cancer diagnosis. Key unique and important features of this study is that ALiX provides an explanation to our medical hypothesis in the form of a list of ranked protein biomarkers that identifies which biomarkers are the most significant drivers of the predicted outcome, a capability that is not currently available in other AI applications. This study identifies a unique profile for stratifying cancer patients and for further stratifying the patients with cancer into subtypes that respond to treatment or not.

Research paper thumbnail of Transforming Growth Factor-Beta 1 Induces Neutrophil Apoptosis in Colorectal Cancer Liver Metastases

Vessel co-option correlates with resistance against anti-angiogenic agents and chemotherapy in co... more Vessel co-option correlates with resistance against anti-angiogenic agents and chemotherapy in colorectal cancer liver metastasis (CRCLM). We previously identified higher intensity of neutrophils in the tumour microenvironment of vessel co-opting CRCLM lesions compared to their angiogenic counterparts. Herein, we demonstrated that over 50% of the neutrophils in vessel co-opting lesions are expressing pro-apoptotic markers including cleaved caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1). Our previous publications suggested upregulation of transforming growth factor-beta (TGFβ1) in the microenvironment of vessel co-option CRCLM. Therefore, we examined the effect of TGFβ1 on the expression of cleaved caspase-3 and PARP-1 in neutrophils in vitro. Significantly, we noticed the upregulation of pro-apoptotic markers upon exposure to TGFβ1. This finding might pave the way to determine the role of neutrophils in developing vessel co-option in CRCLM in the future.

Research paper thumbnail of Targeting Liver Metastases to Potentiate Immunotherapy In MS-stable colorectal cancer- A Scoping Review of Literature

While Immunotherapy has revolutionized the treatment of several cancers such as lung cancer, mela... more While Immunotherapy has revolutionized the treatment of several cancers such as lung cancer, melanoma, and other cancers, most colorectal cancer patients remain resistant. This resistance to immunotherapy may partially stem from the fact that colorectal cancer very commonly metastasizes to the liver. The liver is known to play an immunotolerant role in in other contexts such as organ transplantation, viral disease, and autoimmune disease. Recent studies reveal the mechanisms in which liver metastases restrict the efficacy of immunotherapy. This effect was shown to be reversable in colorectal cancer mice models, when colorectal liver metastases were irradiated. It is possible that targeting liver metastases with locoregional therapies such as ablation, resection or irradiation may reverse the immunosuppressive effect of liver microenvironment and potentiate immunotherapy systemically. During the past decade, several clinical trials are trying to extrapolate the results achieved in an...

Research paper thumbnail of A single center survival analysis of patients with colorectal cancer who underwent next generation sequencing

Journal of Clinical Oncology

31 Background: Colorectal cancer (CRC) remains a lethal diagnosis with an overall 5-year survival... more 31 Background: Colorectal cancer (CRC) remains a lethal diagnosis with an overall 5-year survival rate of 5-10% for patients with unresectable metastatic disease. The advent of next generation sequencing allows tailored systemic therapy to specific mutations with the goal of improving patient survival. McGill University Health Center instituted next generation sequencing in 2019. Our study aims to evaluate survival outcomes in patients who underwent NGS testing. Methods: A retrospective collection of data on all patients with CRC who were presented at both lower gastroenterology and hepatobiliary tumor boards from January 2019 through July 2022 ( n= 498). Survival and was compared between patients who were found to have genetic alterations identified using the Illumina Miseo platform. Statistical Analysis was performed with GraphPad Prism. Results: A total of 321 (64%) patients had NGS performed on either their primary tumor or a metastasis. A total of 229 (71%) CRC patients had gen...

Research paper thumbnail of Extended criteria liver resection: Can noncurative intent resection of colorectal liver metastasis improve survival?

Journal of Clinical Oncology

164 Background: From initially believed to be a palliative diagnosis, CRLM management has ranged ... more 164 Background: From initially believed to be a palliative diagnosis, CRLM management has ranged from nonoperative, resection of only solitary lesions, resection only if 1 cm margin could be obtained, to major hepatectomies with liver regenerative procedures. With a greater understanding of the disease and advances in systemic therapy, clinicians have been able to continuously push the envelope in both resection and local therapies to improve overall survival in patients with CRLM. The constant evolution of management for CRLM raises the question – would patients benefit from a non-curative intent resection by decreasing overall tumor burden? Is there a role for debulking of disease as an extended criterion to improve median survival? Methods: A retrospective study was conducted by identifying patients who consented to participate in the liver disease biobank research program. Consented patients with CRLM evaluated for a two-stage hepatectomy (TSH) between 2012-2020 were identified....

Research paper thumbnail of Histopathological growth patterns determines the outcomes of colorectal cancer liver metastasis that have undergone liver resection

Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis with an overa... more Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis with an overall 5-year survival rate of 5–10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly differing rates of patients survival, and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden and pattern of cancer progression in light of their HGP’s, and to consider their potential effect on surgical decision making. Methods We performed a retrospective multivariate analysis on clinical data from patients with CRCLM (n = 275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring. Results 109 patients (42.2%) were classified as desmoplastic and angiogenic whereas 149 patients (...

Research paper thumbnail of Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1 signaling pathway attenuates vessel co-option in colorectal cancer liver metastases

Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs... more Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs) including angiogenic desmoplastic HGP (DHGP) and non-angiogenic replacement HGP (RHGP). The RHGP lesions obtain their blood supply through vessel co-option, where the cancer cells hijack the pre-existing blood vessels of the surrounding liver tissue. Consequently, anti-angiogenic therapies are less efficacious in CRCLM patients with RHGP lesions. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) and the development of vessel co-opted CRCLM lesions in vivo. However, the mechanisms underlying Ang1 upregulation in vessel co-opting CRCLM lesions are unclear. Herein, we demonstrated that transforming growth factor β1 (TGFβ1) modulates the expression of Ang1 in hepatocytes in vitro. Significantly, pharmaceutical inhibition of integrin alpha-5/beta-1 (ITGα5β1) through ATN-161 impaired TGFβ1-dependent Ang1 expression in vitro and in vivo. Moreover, b...

Research paper thumbnail of The molecular mechanisms underlying neutrophil infiltration in vessel co-opting colorectal cancer liver metastases

Frontiers in Oncology

Colorectal cancer liver metastases (CRCLMs) have two major histopathological growth patterns (HGP... more Colorectal cancer liver metastases (CRCLMs) have two major histopathological growth patterns (HGPs): desmoplastic (DHGP) and replacement (RHGP). The DHGP tumours derive their vasculature by angiogenesis, while the RHGP tumours use vessel co-option. Various studies have associated RHGP tumours with an unfavourable prognosis, as well as high levels of resistance to anti-angiogenic agents and chemotherapy. Recently, we reported higher numbers of neutrophils in the tumour microenvironment (TME) of vessel co-opting tumours compared to their angiogenic counterparts. However, the molecular mechanisms underlying this phenotype are unclear. Herein, we suggested a positive correlation between the expression of angiopoietin-1 (Ang1) in the hepatocytes and the presence of neutrophils in vessel co-opting tumours. Importantly, upregulation of Ang1 in the hepatocytes is associated with the presence of runt-related transcription factor-1 (RUNX1) in the neighboring cancer cells in vitro and in vivo....

Research paper thumbnail of Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Research paper thumbnail of Volumetric Based Quantification of Histopathological Growth Patterns Is Most Predictive of Progression Free Survival Following Resection of Colorectal Liver Metastases

Research paper thumbnail of Eliciting a Systemic Immune Response against Liver Tumors Utilizing Locoregional Therapies - A Systematic Review of Prospective Studies

Research paper thumbnail of Abstract 1580: Cancer cells promote phenotypic alterations in adjacent hepatocytes to facilitate vessel co-option in colorectal cancer liver metastasis

Cancer Research

Vessel co-option is associated with resistance against anti-angiogenic therapy in colorectal canc... more Vessel co-option is associated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opted lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding non-malignant tissue and hijack them to gain access to nutrient. In order to access the sinusoidal vessels, the cancer cells must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, motility, epithelial-mesenchymal transition (EMT) and autophagy pathways in hepatocyte’s displacement by cancer cells. We demonstrated that cancer cells induce the expression of the proteins that associated with upregulation of apoptosis, motility and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observed upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and Actin Related Prote...

Research paper thumbnail of Abstract 5291: Characterizing the interplay between angiogenic and immunoactive factors of hepatocellular carcinoma

Cancer Research

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death globally. Pati... more Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death globally. Patients typically present at an advanced stage and less than 50% reach the maximum 1-year survival rate, when given as first-line treatment, Sorafenib. This highlights the need for early detection and novel therapeutic targets crucial to increase overall survival (OS) for patients with HCC. Given the important role of angiogenesis in HCC from its early stage and its rich immune composition, anti-angiogenic and immune checkpoint inhibitors (ICI), are two therapeutic approaches when combined marked the first treatment in more than a decade to significantly improve the overall survival and progression-free survival in patients with advanced HCC compared to Sorafenib. While the combination of agents inhibiting angiogenesis and ICI have recently entered the clinic, the interplay between angiogenic factors and immunity in the context of this approach remains poorly understood. Here we focus on un...

Research paper thumbnail of Abstract 6154: Distinct immunosuppressive environments elicited in vessel co-opting and angiogenic colorectal cancer liver metastases and changes following treatment

Cancer Research

Colorectal cancer (CRC) is the third most common cancer worldwide and 50% of CRC patients develop... more Colorectal cancer (CRC) is the third most common cancer worldwide and 50% of CRC patients develop liver metastases. Colorectal cancer liver metastases (CRCLM) present as two major histological growth patterns (HGP) that predict response to treatment/survival: 1. angiogenic tumors characterized by a desmoplastic stroma separating CRC cells from the liver parenchyma and are highly angiogenic and 2. co-opting tumors where tumor cells infiltrate the parenchymal cells in the liver and grow by co-opting the sinusoidal blood vessels between the liver cell plates without sprouting angiogenesis. Angiogenic tumors receiving neoadjuvant anti-angiogenics (anti-VEGF) and chemotherapy have more than double the 5-year overall survival compared to patients with co-opting tumors who have received the same neoadjuvant regimen. In addition, our clinical data revealed that anti-angiogenics could negatively affect outcomes in patients with co-opting lesions. The goal of our study is to understand how th...

Research paper thumbnail of Loss of ATAD3A contributes to NAFLD through the accumulation of lipids and damaged mitochondria

Research paper thumbnail of Results from consensus-oriented decision-making process (CODM) for a primary care based biobank: The quebec experience

Population health and epidemiology

Fundamental research at the primary care level is needed. Medical research has been mostly hospit... more Fundamental research at the primary care level is needed. Medical research has been mostly hospitalbased and focused on molecular mechanisms. There is frequently a discordance between primary care based questions and hospital care-based answers. Biobanks, or biorepositories, designed to provide high quality biospecimens and associated data for disease specific research or population studies, have sparked numerous discussions amongst researchers, scientists, policymakers, ethicists, lawyers and even patient advocate groups. In the era of translational research, there has been an increase of biobanks due to higher demand of biospecimens and data enabling translational research. Therefore, the generation of evidence at the primary care level requires substantial networks of primary care practitioners and investigators in the development of a primary care biobank. While there are numerous online resources and courses available to setup a biobank, there is little information available on the "how-to" for integration within an institution or a network. Each biobank's procedures and plans may be particular to a region or an institution, and the "how-to" may likewise differ. The method(s) used around the numerous meetings and discussions amongst experts to initiate a biobank project is not well described or defined in the literature. The purpose of this paper is to explore the cohesion level of different foundational capabilities identified in a biobank framework using the consensus-oriented decision-making (CODM) process in order to provide guidance in the development of a primary care biobank framework. This study is based on a consensus-based theory. A total of six foundational capabilities were discussed and consensus on cohesions was obtained for each capability. With a number of these capabilities, consensus was achieved, after thematic analysis of the transcript and coding of 120 relevant texts, a number of themes were identified. The involvement of participants at the governance of the biobank, the inclusion of participants in the strategy and mission of the primary care based biobank, as well as ensuring the balance of power for inclusive participation of centres in the biobank are some of the descriptive themes identified during cohesion consensus throughout the foundational capabilities. Determining cohesion levels to develop policies and guidelines is an added tool in the development of a biobank as well as facilitating a "successful" implementation

Research paper thumbnail of Abstract A26: Immune profiling and organoids generation of a rare case of prostate cancer liver metastasis

Cancer Immunology Research, 2020

Introduction: Prostate cancer (PCa) is the second most frequent cancer in men and a leading cause... more Introduction: Prostate cancer (PCa) is the second most frequent cancer in men and a leading cause of cancer-related mortality. Despite major advances in immunotherapy, PCa remains a poor responder. Metastatic PCa is responsible for the majority of PCa-associated mortality. Most PCa metastases are multifocal and display a strong bones tropism (91.1% of cases), but PCa metastases can also spread to the lymph nodes (8.7%), lungs (5.7%), liver (4.5%) and brain (1.8%). Liver metastases are associated with worse prognosis but due to their multifocal nature and frequent spreading to other sites, PCa metastases are rarely resected. Therefore, immunologic characterization of these lesions concomitant with generation of research tools derived from these lesions are urgently needed to understand how to intercept disease progression. Methods: A 62-year-old male who previously underwent radical prostatectomy in 2016 was diagnosed in July 2018 with a single liver metastasis (5.3 cm) by MRI. The t...

Research paper thumbnail of Abstract 2834: Metastatic colorectal cancer: characterization of distinct histological growth patterns which demonstrate different response to current treatment regimes

Cancer Research, 2017

Colorectal cancer (CRC) is the third most common cancer in North America, and the third leading c... more Colorectal cancer (CRC) is the third most common cancer in North America, and the third leading cause of cancer-related death. About 50% of patients will be diagnosed with CRC liver metastasis (CRCLM) during the course of their disease. We have identified two major histological growth patterns (HGP) in CRCLM resected from patients. In the desmoplastic HGP (DHGP), the tumor cells are enclosed within a desmoplastic stromal ring, physically separating them from the normal liver tissue. In the replacement HGP (RHGP), the tumor cells replace normal hepatocytes without disrupting adjacent cells or structures within the liver parenchyma. We have recently shown that patients with RHGP lesions who received neoadjuvant bevacizumab plus chemotherapy had a worse pathological response and five-year overall survival. Our group has also shown that RHGP CRCLM is resistant to anti-angiogenic therapy due to it promoting vessel co-option as a means of tumor vascularization, rather than VEGF-dependent ...

Research paper thumbnail of Abstract 1695: Vascularization of colorectal cancer liver metastasis: correlation with growth patterns

Cancer Research, 2016

Colorectal cancer (CRC) is the third leading cause of cancer-related death in North America. Appr... more Colorectal cancer (CRC) is the third leading cause of cancer-related death in North America. Approximately 50% of patients will be diagnosed with CRC liver metastasis (CRLM) during the course of their disease. Untreated, patients will survive for only a few months, but with chemotherapy, a median survival of 20 months can be achieved. At present, no reliable indicators exist to predict outcome or prognosis in treatable patients. Moreover, no biological parameters are currently being considered for patient stratification into different treatment groups. We examined CRCLM resected from patients and have identified two major histologic growth patterns (HGP): a desmoplastic (DHGP) pattern and a replacement (RHGP) pattern where tumor cells replace parenchymal cells in the liver plates. These HGP involve distinct modes of angiogenesis and host cell responses. Namely, liver metastases with a RHGP grow by co-opting the stroma, without hypoxia-induced angiogenesis and with little perturbatio...

Research paper thumbnail of Eukaryotic Translation Initiation Factor 4E–Induced Progression of Primary Human Mammary Epithelial Cells along the Cancer Pathway Is Associated with Targeted Translational Deregulation of Oncogenic Drivers and Inhibitors

Cancer Research, 2007

Pathologic redirection of translational control by constitutive activation of eukaryotic translat... more Pathologic redirection of translational control by constitutive activation of eukaryotic translation initiation factor 4F (eIF4F), the cap-dependent translation initiation apparatus, is an obligatory step in oncogenesis; however, its mechanism remains undefined. Here, we simulate this pro-oncogenic state by overexpressing eIF4E, the rate-limiting component of eIF4F, in primary human mammary epithelial cells (HMECs) and examine the resultant changes in cell biology and gene expression profiles of total and polyribosome-bound mRNA genome wide. Overexpressed eIF4E rescues primary HMECs from telomere-independent growth arrest and disables checkpoints governing S-phase entry as well as apoptosis in HMECs immortalized by telomerase, imparting cells with proliferative and survival autonomy. Although the transcriptional response to increased eIF4E was modest, the translational response was large, selective, and bidirectional. In addition to translational activation of known and novel eIF4E-...