Amal T. Elhaw

Loss of Predicted Cell Adhesion Molecule MPZL3 Promotes EMT in Ovarian Cancer

Abstract Myelin protein zero-like 3 (MPZL3) is an immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, in which the MPZL3 gene resides, is frequently observed in cancer. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, in which both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. Whereas high and low MPZL3-expressing populations are similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely display decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knockdown leads to an increase in EMT gene expression in OVCAR4 and OVCA433 cell lines, a transcript signature that is associated with poor patient outcomes. MPZL3 promotes homotypic cancer cell adhesion, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. Conversely, MPZL3 loss abrogates cell-cycle progression and proliferation, with cells adopting senescence features. This was associated with decreased sensitivity to cisplatin and reduced DNA damage and apoptosis in response to treatment in OVCAR4 cells. Our study suggests that decreased expression of the predicted adhesion molecule MPZL3 is associated with low proliferation but increased metastatic potential during ovarian cancer tumor progression. Significance: This work presents novel findings that decreased expression of the potential cell adhesion molecule MPZL3 is a phenotype of ovarian cancer progression and metastasis.

Aged and BRCA -Mutated Stromal Cells Drive Epithelial Cell Transformation

Abstract The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, presenting critical barriers to the prevention and early detection of this deadly disease. Current models propose that fallopian tube epithelial (FTE) cells transform into serous tubal intraepithelial carcinoma (STIC) precursor lesions and subsequently into HGSOC. In this study, we report that an epigenetically altered mesenchymal stem cell niche, termed high-risk mesenchymal stromal/stem cell (hrMSC), exists prior to STIC lesion formation. hrMSCs are enriched in STIC stroma and contribute to a stromal “field effect” extending beyond the borders of the STIC lesion. hrMSCs promote DNA damage in FTE cells while also fostering FTE cell survival. hrMSCs induce malignant transformation of the FTE, resulting in metastatic cancer in vivo, indicating that hrMSCs promote cancer initiation. hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age. Combined, these findings indicate that hrMSCs can incite ovarian cancer initiation and have important implications for ovarian cancer detection and prevention. Significance: This work demonstrates a critical role of fallopian tube stromal cells in HGSOC initiation with implications for the pathophysiology of HGSOC formation and the development of prevention and early detection strategies critically needed in this disease. Additionally, the identification of stromal-mediated epithelial transformation has broad implications for understanding pan-cancer initiation. See related commentary by Recouvreux and Orsulic, p. 1093