Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition

Abstract

High-grade serous ovarian carcinoma (HGS-OvCa) harbors p53 mutations and can originate from the epithelial cell compartment of the fallopian tube fimbriae. From this site, neoplastic cells detach, survive in the peritoneal cavity, and form cellular clusters that intercalate into the mesothelium to form ovarian and peritoneal masses. To examine the contribution of mutant p53 to phenotypic alterations associated with HGS-OvCA, we developed live-cell microscopy assays that recapitulate these early events in cultured fallopian tube nonciliated epithelial (FNE) cells. Expression of stabilizing mutant variants of p53, but not depletion of endogenous wild-type p53, in FNE cells promoted survival and cell-cell aggregation under conditions of cell detachment, leading to the formation of cell clusters with mesothelium-intercalation capacity. Mutant p53R175H-induced phenotypes were dependent on fibronectin production, α5β1 fibronectin receptor engagement, and TWIST1 expression. These results indicate that FNE cells expressing stabilizing p53 mutants acquire anchorage independence and subsequent mesothelial intercalation capacity through a mechanism involving mesenchymal transition and matrix production. These findings provide important new insights into activities of mutant p53 in the cells of origin of HGS-OvCa.

Fallopian tube precursor lesions of serous ovarian carcinoma require L1CAM for dissemination and metastasis

“…However, growth of L1CAM-wildtype OVCAR8 cells under 3D conditions led to an increase in fibronectin expression that was confirmed by Western blot analysis ( Figure 6A, Supplemental Figure 3A). Previous studies have documented the important roles of fibronectin and Integrin-ɑ5β1 in the establishment of extracellular matrix support for ovarian cancer cells (Iwanicki et al 2016). Consistent with these functions, we observed a strong downregulation of Integrin-ɑ5β1 in the OVCAR8-L1 cells compared to OVCAR8 cells, whereas integrin-β3 was upregulated in OVCAR8-L1, indicating a change in the integrin signaling pattern.…”

Pathogenesis and heterogeneity of ovarian cancer

“…Recent studies indicate that stabilizing TP53 missense mutations, but not loss of endogenous wildtype TP53 , promote secretory cell survival and cell–cell aggregation under anchorage independent growth conditions. This mutant-mediated autocrine matrix deposition leads to the formation of cell clusters with mesothelial-intercalation capacity which is likely necessary for peritoneal dissemination [67 ▪ ]. Interestingly, it appears that the most common TP53 missense mutations, including R273H, R175H, and R248Q, express a large number and high amounts of shorter p53 protein isoforms that are translated from the mutated full-length p53 mRNA.…”

Integrins in the Spotlight of Cancer

“…However, inhibition of the mouse double minute homolog (MDM)-p53 complex by the small inhibitor Nutlin-3 restores sensitivity to temozolomide chemotherapy and reduces α5 expression [120]. In ovarian cancer, mutated p53 enables α5β1 integrin-mediated anchorage independent growth [121]. …”