Post doc, Ottawa hospital research Ins. (OHRI)
Epithelial Ovarian Cancers (EOC) have been reported to arise mainly from the epithelia of the ovarian surface (OSE) and distal fallopian tube. However, the molecular mechanisms underlying the initiation and progression of EOC derived from the OSE remains unclear. The Hippo singling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates YAP protein. Unphosphorylated YAP activates genes involved in cell proliferation and survival, and YAP activation is suppressed by large tumor suppressor family (LATS1 and 2) members. It has been shown that LATS1 is expressed in human ovarian epithelium, but this expression is decreased in the transition to carcinoma, although the role of LATS1 during this process is unknown. In this study, our objective was to explore the consequences of loss of LATS1/2 in OSE cells. OSE cell-specific deletion of Lats1/2 in the mouse ovaries. Our results indicated that ovarian tumors were detected in all injected animals (n=10) after a month. Mice subjected to injection exhibited the tumor in their ovaries and all animals had ascites with metastases spread throughout the peritoneal cavity. Histologically, these tumors derived from the conditional deletion of Lats1/2 resembled high-grade serous carcinoma (HGSC) that is the most aggressive type of human ovarian cancer. Moreover, we found a drug that can use to inhibit tumor growth derived from these mice. Collectively, the data indicate that dysregulation of the Hippo signaling pathway can lead to the initiation and progression of ovarian cancer and loss of LATS1/2 is a potent stimulus for the growth of ovarian serous carcinoma.
Abstract: Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from fallopian tube secretory epithelial cells (FTSECs). However, the molecular mechanisms underlying the initiation and progression of HGSC derived from FTSECs remains unclear. In this study, we found that the Hippo/Yes-associated protein (YAP) signaling pathway has a critical role in the initiation and progression of fallopian tube and ovarian HGSC. Importantly, YAP was overexpressed in inflammatory and cancerous fallopian tube tissues. Further, overexpression of wild-type YAP, or constitutively active YAP in immortalized FTSECs, induced cell proliferation, migration, colony formation and tumorigenesis. Moreover, the Hippo/YAP and the fibroblast growth factor (FGF) signaling pathways formed an autocrine/paracrine-positive feedback loop to drive the progression of the FTSEC-derived HGSC. Evidence in this study strongly suggests that combined therapy with inhibitors of YAP (such as verteporfin) and FGF receptors (such as BGJ398) can provide a novel therapeutic strategy to treat fallopian tube and ovarian HGSC.
Pub.: 15 Sep '15, Pinned: 30 Jun '17
Abstract: Poorly immunogenic tumor cells evade host immunity and grow even in the presence of an intact immune system, but the complex mechanisms regulating tumor immunogenicity have not been elucidated. Here, we discovered an unexpected role of the Hippo pathway in suppressing anti-tumor immunity. We demonstrate that, in three different murine syngeneic tumor models (B16, SCC7, and 4T1), loss of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in tumor cells inhibits tumor growth. Tumor regression by LATS1/2 deletion requires adaptive immune responses, and LATS1/2 deficiency enhances tumor vaccine efficacy. Mechanistically, LATS1/2-null tumor cells secrete nucleic-acid-rich extracellular vesicles, which induce a type I interferon response via the Toll-like receptors-MYD88/TRIF pathway. LATS1/2 deletion in tumors thus improves tumor immunogenicity, leading to tumor destruction by enhancing anti-tumor immune responses. Our observations uncover a key role of the Hippo pathway in modulating tumor immunogenicity and demonstrate a proof of concept for targeting LATS1/2 in cancer immunotherapy.
Pub.: 03 Dec '16, Pinned: 30 Jun '17