Biology subjects

Al-Saad, S.

Publications and source records attributed to Al-Saad, S..

3 recordsLinked to original sources

bioRxiv2025

RHOV is a Detachment-Responsive Rho GTPase Necessary for Ovarian Cancer Peritoneal Metastasis

All ovarian cancer subtypes spread via transcoelomic metastasis, where cells disseminate into the peritoneal fluid, resist anoikis, and form multicellular aggregates that invade the peritoneum. This represents the main driver of morbidity and mortality for peritoneal cancer patients. Mechanisms necessary for cancer cells to survive matrix detachment and initiate transcoelomic metastasis remain poorly defined. To address this, we identified a conserved detachment-sensitive gene signature activated shortly after matrix-detachment across multiple ascites-derived cancer cell lines. RHOV, an atypical, constitutively active and understudied member of the Rho GTPase family, emerged as a top upregulated transcript, which was confirmed in patient ascites-derived tumor cells. Functionally, loss of RHOV impairs anoikis resistance, multicellular aggregate integrity, migration and invasion, and completely abolishes transcoelomic tumor progression in vivo. RHOV enhances c-Jun signaling and cytoskeletal remodeling, which is dependent on both RHOV GTP-binding and membrane localization. These findings define RHOV as a novel detachment-sensitive Rho GTPase and establish RHOV as a critical regulator of peritoneal metastasis for the first time.

cancer biology↗

bioRxiv2024

Loss of the predicted cell adhesion molecule MPZL3 promotes EMT and chemoresistance in ovarian cancer

Myelin protein zero-like 3 (MPZL3) is an Immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, where the MPZL3 gene resides, is frequently observed in cancer, and MPZL3 copy number alterations are frequently detected in tumor specimens. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, where both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. While high and low MPZL3 expressing populations were similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely displayed decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knock-down leads to strong upregulation of vimentin and an EMT gene signature that is associated with poor patient outcomes. Moreover, MPZL3 is necessary for homotypic cancer cell adhesion, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. In addition, MPZL3 loss abrogated cell cycle progression and proliferation. This was associated with increased resistance to Cisplatin and Olaparib and reduced DNA damage and apoptosis in response to these agents. Enhanced Cisplatin resistance was further validated in vivo. These data demonstrate for the first time that MPZL3 acts as an adhesion molecule and that MPZL3 loss results in EMT, decreased proliferation, and drug resistance in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients.

cancer biology↗

bioRxiv2024

Comparative analysis of kidney transplantation modeled using precision-cut kidney slices and kidney transplantation in pigs

Kidney transplants are at risk for so far unavoidable ischemia-reperfusion injury. Several experimental kidney transplantation models are available to study this injury, but all have their own limitations. Here, we describe precision-cut kidney slices (PCKS) as a novel model of kidney ischemia-reperfusion injury in comparison with pig and human kidney transplantation. Following bilateral nephrectomy in pigs, we applied warm ischemia (1h), cold ischemia (20h) and a reperfusion period (4h) to one whole kidney undergoing transplantation to a recipient pig and, in parallel, established PCKS undergoing ischemia and modeled reperfusion. Histopathological assessment revealed the presence of some but not all morphological features of tubular injury in PCKS as seen in pig kidney transplantation. RNAseq demonstrated that the majority of changes occurred after reperfusion only, with a partial overlap between PCKS and kidney transplantation, with some differences in transcriptional response attributable to systemic inflammatory responses and immune cell migration. Comparison of PCKS and pig kidney transplantation with RNAseq data from human kidney biopsies by gene set enrichment analysis revealed that both PCKS and pig kidney transplantation reproduced the post-reperfusion pattern of human kidney transplantation. In contrast, only post-cold ischemia PCKS and pig kidney partially resembled the gene set of human acute kidney injury. Overall, the present study established that a PCKS protocol can model kidney transplantation and its reperfusion-related damage on a histological and a transcriptomic level. PCKS may thus expand the toolbox for developing novel therapeutic strategies against ischemia-reperfusion injury.

pathology↗