Irene Romayor - Academia.edu (original) (raw)

Papers by Irene Romayor

Biomedicines

The successful reprogramming of human somatic cells into induced pluripotent stem cells (hiPSCs) ... more The successful reprogramming of human somatic cells into induced pluripotent stem cells (hiPSCs) represented a turning point in the stem cell research field, owing to their ability to differentiate into any cell type with fewer ethical issues than human embryonic stem cells (hESCs). In mice, PSCs are thought to exist in a naive state, the cell culture equivalent of the immature pre-implantation embryo, whereas in humans, PSCs are in a primed state, which is a more committed pluripotent state than a naive state. Recent studies have focused on capturing a similar cell stage in human cells. Given their earlier developmental stage and therefore lack of cell-of-origin epigenetic memory, these cells would be better candidates for further re-differentiation, use in disease modeling, regenerative medicine and drug discovery. In this study, we used primed hiPSCs and hESCs to evaluate the successful establishment and maintenance of a naive cell stage using three different naive-conversion med...

Supplemental Data (3 Figures) from the paper entitled <i>"Silencing of tumor DDR1 redu... more Supplemental Data (3 Figures) from the paper entitled <i>"Silencing of tumor DDR1 reduces liver metastasis by colon carcinoma through inhibition of stromal reaction"</i>

The Breast Journal

Discoidin domain receptor 2 (DDR2) is arising as a promising therapeutic target in breast carcino... more Discoidin domain receptor 2 (DDR2) is arising as a promising therapeutic target in breast carcinoma (BC). The ability of DDR2 to bind to collagen promotes protumoral responses in cancer cells that influence the tumor microenvironment (TME). Nonetheless, the interrelation between DDR2 expression and TME modulation during BC progression remains poorly known. For this reason, we aim to evaluate the correlation between intratumoral expression of DDR2 and the infiltration of the main TME cell populations, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs). First, collagen and DDR2 expression levels were analyzed in human invasive BC samples. Then, DDR2 status correlation with tumor aggressiveness and patient survival were retrieved from different databases. Subsequently, the main pathways, cell types, and tissues correlated with DDR2 expression in BC were obtained through bioinformatics approach. Finally, we studied the association of DDR2 expression with the r...

Biomolecules & Therapeutics

Liver colonization is initiated through the interplay between tumor cells and adhesion molecules ... more Liver colonization is initiated through the interplay between tumor cells and adhesion molecules present in liver sinusoidal endothelial cells (LSECs). This crosstalk stimulates tumor COX-2 upregulation and PGE2 secretion. To elucidate the role of the LSEC intercellular adhesion molecule-1 (ICAM-1) in the prometastatic response exerted by tumor and stromal COX-2, we utilized celecoxib (CLX) as a COX-2 inhibitory agent. We analyzed the in vitro proliferative and secretory responses of murine C26 colorectal cancer (CRC) cells to soluble ICAM-1 (sICAM-1), cultured alone or with LSECs, and their effect on LSEC and hepatic stellate cell (HSC) migration and in vivo liver metastasis. CLX reduced sICAM-1-stimulated COX-2 activation and PGE2 secretion in C26 cells cultured alone or cocultured with LSECs. Moreover, CLX abrogated sICAM-1-induced C26 cell proliferation and C26 secretion of promigratory factors for LSECs and HSCs. Interestingly, CLX reduced the protumoral response of HSC, reducing their migratory potential when stimulated with C26 secretomes and impairing their secretion of chemotactic factors for LSECs and C26 cells and proliferative factors for C26 cells. In vivo, CLX abrogated the prometastatic ability of sICAM-1-activated C26 cells while reducing liver metastasis. COX-2 inhibition blocked the creation of a favorable tumor microenvironment (TME) by hindering the intratumoral recruitment of activated HSCs and macrophages in addition to the accumulation of fibrillar collagen. These results point to COX-2 being a key modulator of processes initiated by host ICAM-1 during tumor cell/LSEC/HSC crosstalk, leading to the creation of a prometastatic TME in the liver.

Intercellular adhesion molecule (ICAM)-1, is a transmembrane glycoprotein of the immunoglobulin (... more Intercellular adhesion molecule (ICAM)-1, is a transmembrane glycoprotein of the immunoglobulin (Ig)-like superfamily, consisting of five extracellular Ig‐like domains, a transmembrane domain and a short cytoplasmic tail. ICAM-1 is expressed in various cell types, including endothelial cells and leukocytes, and is involved in several physiological processes. Furthermore, it has additionally been reported to be expressed in various cancer cells, including melanoma, colorectal cancer and lymphoma. The majority of studies to date have focused on the expression of the ICAM‐1 on the surface of tumor cells, without research into ICAM‐1 expression at sites of metastasis. Cancer cells frequently metastasize to the liver, due to its unique physiology and specialized liver sinusoid capillary network. Liver sinusoidal endothelial cells constitutively express ICAM‐1, which is upregulated under inflammatory conditions. Furthermore, liver ICAM‐1 may be important during the development of liver me...

Colorectal cancer (CRC) colonization of the liver and its further metastatic growth are the resul... more Colorectal cancer (CRC) colonization of the liver and its further metastatic growth are the result of complex interaction between the tumor cell, the collagenous extracellular matrix (ECM) and the hepatic sinusoidal cells (SCs). Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor activated by collagen and a bad prognosis factor in cancer. DDR1 signaling regulates key cell functions for tumor development, such as proliferation, migration, invasion and metalloproteinases (MMPs) secretion. However, the mechanisms underlying the implication of DDR1 in the conformation of the metastatic niche in the liver remain poorly known. In this study, we used an experimental model of liver metastasis from CRC to investigate the role of DDR1 in the context of the pro-metastatic crosstalk between tumor cells and the hepatic stroma. Bioinformatics and immunohistochemical analysis revealed that DDR1 was highly expressed in tumor tissues from patients with primary CRC and hepatic CRC metast...

Scientific Reports

Liver metastasis depends on the collagenous microenvironment generated by hepatic sinusoidal cell... more Liver metastasis depends on the collagenous microenvironment generated by hepatic sinusoidal cells (SCs). DDR1 is an atypical collagen receptor linked to tumor progression, but whether SCs express DDR1 and its implication in liver metastasis remain unknown. Freshly isolated hepatic stellate cells (HSCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs), that conform the SCs, expressed functional DDR1. HSCs expressed the largest amounts. C26 colon carcinoma secretomes increased DDR1 phosphorylation in HSCs and KCs by collagen I. Inhibition of kinase activity by DDR1-IN-1 or mRNA silencing of DDR1 reduced HSCs secretion of MMP2/9 and chemoattractant and proliferative factors for LSECs and C26 cells. DDR1-IN-1 did not modify MMP2/9 in KCs or LSECs secretomes, but decreased the enhancement of C26 migration and proliferation induced by their secretomes. Gene array showed that DDR1 silencing downregulated HSCs genes for collagens, MMPs, interleukins and chemokines. Sile...

Cell Adhesion & Migration

DDR1 is a receptor tyrosine kinases for collagen and an adverse prognostic factor in primary and ... more DDR1 is a receptor tyrosine kinases for collagen and an adverse prognostic factor in primary and metastatic tumors.Despite this, DDR1 signaling and its functional consequences in tumor development remain unclear. RT-PCR and Western blot show that A375, colon carcinoma HT29 and liver carcinoma SK-HEP human cell lines express functional DDR1 that phosphorylates in response to collagen type I. Chemical inhibition of DDR1 phosphorylation or DDR1 mRNA silencing reduced AKT and ERK phosphorylation, expression of ICAM1 and VCAM1, Ki67 and secretion of MMP9. DDR1 silenced cells showed reduced adhesion to collagen type I, MMP-dependent invasion, and chemotactic and proliferative responses to collagen type I. Our work indicates an essential role for DDR1 signaling in key prometastatic features of collagen type I in human carcinoma cells.

Scientific Reports

Oncology Reports

The liver is a common site for the metastatic spread of primary malignancies including colorectal... more The liver is a common site for the metastatic spread of primary malignancies including colorectal cancer, and liver metastasis is a main cause of death in cancer patients. This is due to the complexity of the interactions taking place in the liver between tumor and stromal cells. In fact, cancer-associated fibroblasts (CAFs) have been shown to support tumor growth through the CXCL12/CXCR4 axis. However, along with cancer cells, myeloid-derived suppressor cells (MDSCs), immature dendritic cells with immunosuppressive potential, also express CXCR4. It has recently been demonstrated that reducing CXCL12 availability in the tumor microenvironment decreases liver metastasis. Therefore, blocking CXCL12 chemokine receptor CXCR4 may be a successful approach to diminish the metastatic spread of colorectal cancer to the liver. However, the subjacent mechanisms by which this chemokine influences the tumor are not fully understood. Thus, in order to uncover the role of CXCR4 during tumor cell/liver fibroblast crosstalk driving liver metastasis, the CXCR4 antagonist AMD3100 was used for in vitro studies and in an in vivo approach using an orthotopic model of liver metastasis in immune competent mice through intrasplenic injection of grafted C26 cells. In vitro blockage of CXCR4 led to an impaired migratory potential of tumor and hepatic stellate cells (HSCs) and a reduced tumor response to CXCL12. In vivo administration of AMD3100 to tumor-bearing mice resulted in attenuated metastatic development in the liver, which was accompanied by an impaired infiltration of αSMA-expressing cells within the tumors. In addition, a reduced CD11 + Ly6G + cell count in the liver was directly correlated with a reduction in MDSC numbers in the blood of AMD3100-treated mice compared to the vehicle-treated mice. Therefore, disruption of the CXCR4/CXCL12 axis by CXCR4 antagonist AMD3100 blocked the contribution of both cancer and stromal cells to the metastatic cascade in the liver.

Scienctific Reports, 2019

The prometastatic stroma generated through tumor cells/host cells interaction is critical for met... more The prometastatic stroma generated through tumor cells/host cells interaction is critical for metastatic growth. To elucidate the role of ICAM-1 on the crosstalk between tumor and primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), implicated in tumor adhesion and angiogenesis, we performed in vitro cocultures and an in vivo model of liver metastasis of colorectal cancer (CRC). ICAM-1 blockade in the LSECs decreased the adhesion and transmigration of tumor cells through an LSec in vitro and vivo. Cocultures of C26 cells and LSECs contained higher amounts of IL-1β, IL-6, PGE-2, TNF-α and ICAM-1 than monocultures. C26 cells incubated with sICAM-1 secreted higher amounts of PGE-2, IL-6, VEGF, and MMPs, while enhanced the migration of LSECs and HSCs. HSCs cultures activated by media from C26 cells pretreated with sICAM-1 contained the largest amounts of VEGF and MMPs. C26 cell activation with sICAM-1 enhanced their metastasizing potential in vivo, while tumor LFA-1 blockade reduced tumor burden and LSECs and HSC-derived myofibroblasts recruitment. In vivo ICAM-1 silencing produced similar results. These findings uncover LSEC ICAM-1 as a mediator of the CRC metastatic cascade in the liver and identifies it as target for the inhibition of liver colonization and metastatic progression. Colorectal cancer (CRC) represents one of the most prevalent malignancies worldwide 1. Primary lesions are usually resectable, whereas prognosis worsens when distant metastases are detected. As many as 15% of CRC patients present hepatic metastasis at the time of diagnosis and 50% will develop liver metastasis after their primary resection 2. Moreover, 30-40% of patients with advanced colorectal cancer will develop metastases to the liver only 3 , pointing out metastasis as a promising target for antitumor treatments to improve the survival of colorectal cancer patients. Growing evidence supports a significant role for stromal cells of the host organ in the initiation and progression of the metastatic cascade 4 , and the implication of adhesion molecules in the crosstalk between tumor and host cells is currently under the spotlight 5. Indeed, changes in the expression of adhesion molecules in the tumor cell surface facilitate tumor dissemination, colonization 6 and metastatic growth in the liver 7. However, the involvement of adhesion molecules from the host organ in the metastatic cascade needs further attention. Formation of clinically relevant metastases depends on the generation of a favorable local microenviron-ment different from that of the neighboring tissues, which allows metastatic cell retention, survival, and growth 8. An inflammatory response boosts tumor growth and metastasis and thus represents one of the hallmarks of