S. Tabariès - Academia.edu (original) (raw)

Papers by S. Tabariès

Oncogene, 2016

TJs are large intercellular adhesion complexes that maintain cell polarity in normal epithelia an... more TJs are large intercellular adhesion complexes that maintain cell polarity in normal epithelia and endothelia. During the metastatic process, TJs must be ‘loosened’ or dismantled in cancer cells to enable migration and dissemination. Diminished TJ integrity must also occur within endothelial cells to allow intravasation and extravasation of cancer cells across endothelial barriers. Claudins are critical components of TJs, forming homo- and heteromeric interactions between the adjacent cells, which have been implicated as key modulators of carcinogenesis and metastasis. Numerous epithelial-derived cancers display altered claudin expression patterns and certain claudins can now be used as biomarkers to predict patient prognosis. Moreover, claudins have been functionally implicated in numerous steps of the metastatic cascade. The distinct roles played by claudins during the cancer progression to metastatic disease are just starting to be elucidated. A more complete understanding of the mechanisms through which claudins augment cancer metastasis is required to develop new therapeutic agents against this family of proteins. In this review, we will summarize the relationship between the claudin expression and clinical outcomes in diverse cancers, discuss tumor intrinisic roles through which claudins regulate metastasis and explore claudin-mediated functions within stromal cells that influence the metastatic process. Finally, we will consider possible strategies for targeting claudins that have the potential to improve the management of metastatic cancer.

Oncogene, 2010

The liver represents the third most frequent site of metastasis in patients with breast cancer. W... more The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1-and a 5 b 1-integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.

Nature Structural Biology - NATURE STRUCT BIOLOGY, 1999

The aggregation and membrane fusion properties of annexin II are modulated by the association wit... more The aggregation and membrane fusion properties of annexin II are modulated by the association with a regulatory light chain called p11. p11 is a member of the S100 EF-hand protein family, which is unique in having lost its calcium-binding properties.We report the first structure of a complex between p11 and its cognate peptide, the N-terminus of annexin II, as well as that of p11 alone. The basic unit for p11 is a tight, non-covalent dimer. In the complex, each annexin II peptide forms hydrophobic interactions with both p11 monomers, thus providing a structural basis for high affinity interactions between an S100 protein and its target sequence. Finally, p11 forms a disulfide-linked tetramer in both types of crystals thus suggesting a model for an oxidized form of other S100 proteins that have been found in the extracellular milieu.

Poster Presentations - Proffered Abstracts, 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 tumor was surgically resected and tumor tissue along with peripheral blood was collected and processed for in-depth immunologic/molecular characterization and generation of tumor models. The study was done in accordance with the guidelines approved by MUHC IRB. Prior written informed consent was obtained from the subject to participate in the study (protocol: SDR-11-066). Results: The prostatic origin of the tumor mass was confirmed by positivity for PSMA and NKX3.1 expression. Patient-derived xenografts, 2D cell and organoid cultures were generated and immunophenotyping of the innate and adaptive peripheral and tumor-infiltrating immune cells subsets was performed. Genomic alterations are currently being characterized by multiplex ligation-dependent probe amplification (MLPA). Additionally, chromatin accessibility-based characterization of the gene regulatory network of tumor luminal cells (CD49-CD26+) using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) together with RNA-seq is presently under way. Conclusions: Our collaborative effort will provide the much-needed research tools required to model and understand the processes leading to the rare, but lethal, progression from a localized PCa lesion to liver metastases. Combined with other ongoing research efforts, we believe this case will help us understand the molecular basis to the liver tropism of a subset of PCa metastases and ultimately provide biomarkers for early identification of patients with increased metastatic potential as well as a basis to determine the appropriate immunotherapy modality for metastatic patients. Citation Format: Aurelie Y. Le Page, Anna de Polo, K-P Guerard, A. Lazaris, S.K. Petrillo, W. Ebrahimizadeh, S. Tabaries, S. Shinde-Jadhav, A. Feldiorean, N. Boufaeid, W. Kassouf, C. Piccirillo, P.M. Siegel, A. Aprikian, A. Gregorieff, J. Lapointe, P. Metrakos, D.P. Labbe. Immune profiling and organoids generation of a rare case of prostate cancer liver metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A26.

Cancer Research, 2004

The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a ... more The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a decreased PTC expression in superficial papillary bladder tumors led us to hypothesize that it could also be involved in this cancer. To further investigate this hypothesis, we submitted Ptc ϩ/Ϫ heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water. Preneoplastic and neoplastic changes were observed significantly earlier in the Ptc ؉/؊ than in the wild-type mice. Our data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder cancer.

Cancer Research, 2004

The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a ... more The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a decreased PTC expression in superficial papillary bladder tumors led us to hypothesize that it could also be involved in this cancer. To further investigate this hypothesis, we submitted Ptc ϩ/Ϫ heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water. Preneoplastic and neoplastic changes were observed significantly earlier in the Ptc ؉/؊ than in the wild-type mice. Our data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder cancer.

genesis, 2007

Analysis of the Hoxa5 À/À mutants has revealed the critical role of Hoxa5 in survival, specificat... more Analysis of the Hoxa5 À/À mutants has revealed the critical role of Hoxa5 in survival, specification of axial identity, and ontogeny of organs, including the respiratory tract. The presence of the selection cassette in the original Hoxa5 À/À mutation may interfere with the interpretation of the phenotypes. To circumvent this aspect and to bypass the lethality of the Hoxa5 mutation, we have designed a conditional approach and generated Hoxa5 allelic variants. The conditional allele (Hoxa5 floxed ) behaves as a wild-type allele. In contrast, both the Hoxa5 D and the Hoxa5 floxneo alleles are characterized by the loss of the functional transcript and protein, the lethality due to lung defects and the skeletal homeotic transformations similar to those of the Hoxa5 À/À mutants. Analysis of neighboring Hox gene expression patterns in the Hoxa5 mutants produced further confirmed that the Hoxa5 allelic variants are true null alleles. genesis 45:218-228, 2007.

Structure, 2000

Background: S100C (S100A11) is a member of the S100 calcium-binding protein family, the function ... more Background: S100C (S100A11) is a member of the S100 calcium-binding protein family, the function of which is not yet entirely clear, but may include cytoskeleton assembly and dynamics. S100 proteins consist of two EF-hand calcium-binding motifs, connected by a flexible loop. Like several other members of the family, S100C forms a homodimer. A number of S100 proteins form complexes with annexins, another family of calcium-binding proteins that also bind to phospholipids. Structural studies have been undertaken to understand the basis of these interactions.

Nature structural biology, 1999

The aggregation and membrane fusion properties of annexin II are modulated by the association wit... more The aggregation and membrane fusion properties of annexin II are modulated by the association with a regulatory light chain called p11.p11 is a member of the S100 EF-hand protein family, which is unique in having lost its calcium-binding properties. We report the first structure of a complex between p11 and its cognate peptide, the N-terminus of annexin II, as well as that of p11 alone. The basic unit for p11 is a tight, non-covalent dimer. In the complex, each annexin II peptide forms hydrophobic interactions with both p11 monomers, thus providing a structural basis for high affinity interactions between an S100 protein and its target sequence. Finally, p11 forms a disulfide-linked tetramer in both types of crystals thus suggesting a model for an oxidized form of other S100 proteins that have been found in the extracellular milieu.

Mechanisms of Development, 2009

embryonic stem cells and their transitions during differentiation are regulated by miRNAs, we ana... more embryonic stem cells and their transitions during differentiation are regulated by miRNAs, we analysed the miRNA expression profile of ES cells as they differentiate toward an extra-embryonic ectoderm fate (trophoblast) following acute downregulation of the stem cell master regulator Oct4. The expression levels of approximately 5% of the identified miRNAs changed markedly upon Oct4 downregulation. We are currently performing experiments designed to interfere with the function of these developmentally-regulated miRNAs, and investigating the roles that specific miRNAs play in proliferation and differentiation of ES cells.

Oncogene, 2011

The liver represents the third most frequent site of metastasis in patients with breast cancer. W... more The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1 -and a 5 b 1 -integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.

Oncogene, 2016

TJs are large intercellular adhesion complexes that maintain cell polarity in normal epithelia an... more TJs are large intercellular adhesion complexes that maintain cell polarity in normal epithelia and endothelia. During the metastatic process, TJs must be ‘loosened’ or dismantled in cancer cells to enable migration and dissemination. Diminished TJ integrity must also occur within endothelial cells to allow intravasation and extravasation of cancer cells across endothelial barriers. Claudins are critical components of TJs, forming homo- and heteromeric interactions between the adjacent cells, which have been implicated as key modulators of carcinogenesis and metastasis. Numerous epithelial-derived cancers display altered claudin expression patterns and certain claudins can now be used as biomarkers to predict patient prognosis. Moreover, claudins have been functionally implicated in numerous steps of the metastatic cascade. The distinct roles played by claudins during the cancer progression to metastatic disease are just starting to be elucidated. A more complete understanding of the mechanisms through which claudins augment cancer metastasis is required to develop new therapeutic agents against this family of proteins. In this review, we will summarize the relationship between the claudin expression and clinical outcomes in diverse cancers, discuss tumor intrinisic roles through which claudins regulate metastasis and explore claudin-mediated functions within stromal cells that influence the metastatic process. Finally, we will consider possible strategies for targeting claudins that have the potential to improve the management of metastatic cancer.

Oncogene, 2010

The liver represents the third most frequent site of metastasis in patients with breast cancer. W... more The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1-and a 5 b 1-integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.

Nature Structural Biology - NATURE STRUCT BIOLOGY, 1999

The aggregation and membrane fusion properties of annexin II are modulated by the association wit... more The aggregation and membrane fusion properties of annexin II are modulated by the association with a regulatory light chain called p11. p11 is a member of the S100 EF-hand protein family, which is unique in having lost its calcium-binding properties.We report the first structure of a complex between p11 and its cognate peptide, the N-terminus of annexin II, as well as that of p11 alone. The basic unit for p11 is a tight, non-covalent dimer. In the complex, each annexin II peptide forms hydrophobic interactions with both p11 monomers, thus providing a structural basis for high affinity interactions between an S100 protein and its target sequence. Finally, p11 forms a disulfide-linked tetramer in both types of crystals thus suggesting a model for an oxidized form of other S100 proteins that have been found in the extracellular milieu.

Poster Presentations - Proffered Abstracts, 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 tumor was surgically resected and tumor tissue along with peripheral blood was collected and processed for in-depth immunologic/molecular characterization and generation of tumor models. The study was done in accordance with the guidelines approved by MUHC IRB. Prior written informed consent was obtained from the subject to participate in the study (protocol: SDR-11-066). Results: The prostatic origin of the tumor mass was confirmed by positivity for PSMA and NKX3.1 expression. Patient-derived xenografts, 2D cell and organoid cultures were generated and immunophenotyping of the innate and adaptive peripheral and tumor-infiltrating immune cells subsets was performed. Genomic alterations are currently being characterized by multiplex ligation-dependent probe amplification (MLPA). Additionally, chromatin accessibility-based characterization of the gene regulatory network of tumor luminal cells (CD49-CD26+) using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) together with RNA-seq is presently under way. Conclusions: Our collaborative effort will provide the much-needed research tools required to model and understand the processes leading to the rare, but lethal, progression from a localized PCa lesion to liver metastases. Combined with other ongoing research efforts, we believe this case will help us understand the molecular basis to the liver tropism of a subset of PCa metastases and ultimately provide biomarkers for early identification of patients with increased metastatic potential as well as a basis to determine the appropriate immunotherapy modality for metastatic patients. Citation Format: Aurelie Y. Le Page, Anna de Polo, K-P Guerard, A. Lazaris, S.K. Petrillo, W. Ebrahimizadeh, S. Tabaries, S. Shinde-Jadhav, A. Feldiorean, N. Boufaeid, W. Kassouf, C. Piccirillo, P.M. Siegel, A. Aprikian, A. Gregorieff, J. Lapointe, P. Metrakos, D.P. Labbe. Immune profiling and organoids generation of a rare case of prostate cancer liver metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A26.

Cancer Research, 2004

The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a ... more The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a decreased PTC expression in superficial papillary bladder tumors led us to hypothesize that it could also be involved in this cancer. To further investigate this hypothesis, we submitted Ptc ϩ/Ϫ heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water. Preneoplastic and neoplastic changes were observed significantly earlier in the Ptc ؉/؊ than in the wild-type mice. Our data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder cancer.

Cancer Research, 2004

The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a ... more The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a decreased PTC expression in superficial papillary bladder tumors led us to hypothesize that it could also be involved in this cancer. To further investigate this hypothesis, we submitted Ptc ϩ/Ϫ heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water. Preneoplastic and neoplastic changes were observed significantly earlier in the Ptc ؉/؊ than in the wild-type mice. Our data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder cancer.

genesis, 2007

Analysis of the Hoxa5 À/À mutants has revealed the critical role of Hoxa5 in survival, specificat... more Analysis of the Hoxa5 À/À mutants has revealed the critical role of Hoxa5 in survival, specification of axial identity, and ontogeny of organs, including the respiratory tract. The presence of the selection cassette in the original Hoxa5 À/À mutation may interfere with the interpretation of the phenotypes. To circumvent this aspect and to bypass the lethality of the Hoxa5 mutation, we have designed a conditional approach and generated Hoxa5 allelic variants. The conditional allele (Hoxa5 floxed ) behaves as a wild-type allele. In contrast, both the Hoxa5 D and the Hoxa5 floxneo alleles are characterized by the loss of the functional transcript and protein, the lethality due to lung defects and the skeletal homeotic transformations similar to those of the Hoxa5 À/À mutants. Analysis of neighboring Hox gene expression patterns in the Hoxa5 mutants produced further confirmed that the Hoxa5 allelic variants are true null alleles. genesis 45:218-228, 2007.

Structure, 2000

Background: S100C (S100A11) is a member of the S100 calcium-binding protein family, the function ... more Background: S100C (S100A11) is a member of the S100 calcium-binding protein family, the function of which is not yet entirely clear, but may include cytoskeleton assembly and dynamics. S100 proteins consist of two EF-hand calcium-binding motifs, connected by a flexible loop. Like several other members of the family, S100C forms a homodimer. A number of S100 proteins form complexes with annexins, another family of calcium-binding proteins that also bind to phospholipids. Structural studies have been undertaken to understand the basis of these interactions.

Nature structural biology, 1999

The aggregation and membrane fusion properties of annexin II are modulated by the association wit... more The aggregation and membrane fusion properties of annexin II are modulated by the association with a regulatory light chain called p11.p11 is a member of the S100 EF-hand protein family, which is unique in having lost its calcium-binding properties. We report the first structure of a complex between p11 and its cognate peptide, the N-terminus of annexin II, as well as that of p11 alone. The basic unit for p11 is a tight, non-covalent dimer. In the complex, each annexin II peptide forms hydrophobic interactions with both p11 monomers, thus providing a structural basis for high affinity interactions between an S100 protein and its target sequence. Finally, p11 forms a disulfide-linked tetramer in both types of crystals thus suggesting a model for an oxidized form of other S100 proteins that have been found in the extracellular milieu.

Mechanisms of Development, 2009

embryonic stem cells and their transitions during differentiation are regulated by miRNAs, we ana... more embryonic stem cells and their transitions during differentiation are regulated by miRNAs, we analysed the miRNA expression profile of ES cells as they differentiate toward an extra-embryonic ectoderm fate (trophoblast) following acute downregulation of the stem cell master regulator Oct4. The expression levels of approximately 5% of the identified miRNAs changed markedly upon Oct4 downregulation. We are currently performing experiments designed to interfere with the function of these developmentally-regulated miRNAs, and investigating the roles that specific miRNAs play in proliferation and differentiation of ES cells.

Oncogene, 2011

The liver represents the third most frequent site of metastasis in patients with breast cancer. W... more The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1 -and a 5 b 1 -integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.