Biology subjects

Tang, P. W.

Publications and source records attributed to Tang, P. W..

4 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

GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15

ObjectiveWe previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3s pro-tumorigenic function. MethodsGPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. ResultsGPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-{beta} growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. ConclusionsWe show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.

cancer biology↗

bioRxiv2021

HuR -dependent SOD2 protein synthesis is an early adaptation of ovarian cancer cells in response to anchorage independence

During metastasis, cancer cells must adapt to survive a loss of anchorage and evade anoikis. An important pro-survival adaptation is the ability of metastatic tumor cells to increase their antioxidant capacity and restore cellular redox balance. Although much is known about the transcriptional regulation of antioxidant enzymes in response to stress, how cells rapidly adapt to alter antioxidant enzyme levels is less well understood. Using ovarian cancer cells as a model, we demonstrate that an increase in protein expression of the mitochondrial superoxide dismutase SOD2 is a very early event initiated in response to cellular detachment. SOD2 protein synthesis is rapidly induced within 0.5-2 hours of matrix detachment, and polyribosome profiling demonstrates an increase in the number of ribosomes bound to SOD2 mRNA, indicating an increase in SOD2 translation in response to anchorage-independence. Mechanistically, we find that anchorage-independence specifically induces cytosolic accumulation of the RNA binding protein HuR/ELAVL1 and leads to increased HuR binding to SOD2 mRNA. Using HuR siRNA-mediated knock-down, we show that the presence of HuR is necessary for the increase in SOD2 mRNA association with the heavy polyribosome fraction and SOD2 protein synthesis observed in anchorage-independence. Cellular detachment activates the stress-response protein kinase p38 MAPK, which is necessary for HuR-SOD2 mRNA binding and optimal increases in SOD2 protein expression. These findings illustrate a novel post-transcriptional regulatory mechanisms of SOD2, enabling cells to rapidly increase their mitochondrial antioxidant capacity as an acute response to anchorage-independence.

cancer biology↗