We previously proposed a dualistic model for ovarian serous carcinogenesis. One pathway involves the stepwise development of invasive micropapillary serous carcinoma (MPSC) from serous borderline tumor (atypical proliferative serous tumor) to noninvasive and then invasive MPSC. The carcinomas that develop in this fashion are characterized by low-grade nuclei and frequent K-ras mutations. They generally pursue an indolent course. In the other pathway conventional serous carcinoma (CSC) develops from the ovarian surface epithelium without what appears to be intermediate stages. These tumors display high-grade nuclei, wild-type K-ras, and are very aggressive. Some of these CSCs display micropapillary architecture and simulate invasive MPSCs. This raises the possibility that these CSCs develop from an invasive MPSC. To address this question we reviewed 31 moderately and poorly differentiated CSCs and identified 7 with morphological features of invasive MPSC. These seven tumors exhibited micropapillary architecture in at least 25% of the tumor but contained high-grade nuclei. The 31 tumors were assessed for K-ras mutations using digital polymerase chain reaction-based analysis. Despite their micropapillary architecture, all 7 CSCs with micropapillary features contained wild-type K-ras as did the other 24 pure CSCs. The results indicate that CSCs with micropapillary features are not derived from invasive MPSCs. The molecular findings also support the view that ovarian serous carcinomas should be graded as low- and high-grade tumors.
Background Endometriosis is a common, complex disorder which is underrecognized and subject to prolonged delays in diagnosis. It is accompanied by significant changes in the eutopic endometrial lining. Methods We have undertaken the first single-cell RNA-sequencing (scRNA-Seq) comparison of endometrial tissues in freshly collected menstrual effluent (ME) from 33 subjects, including confirmed endometriosis patients (cases) and controls as well as symptomatic subjects (who have chronic symptoms suggestive of endometriosis but have not been diagnosed). Results We identify a unique subcluster of proliferating uterine natural killer (uNK) cells in ME-tissues from controls that is almost absent from endometriosis cases, along with a striking reduction of total uNK cells in the ME of cases (p < 10−16). In addition, an IGFBP1+ decidualized subset of endometrial stromal cells are abundant in the shed endometrium of controls when compared to cases (p < 10−16) confirming findings of compromised decidualization of cultured stromal cells from cases. By contrast, endometrial stromal cells from cases are enriched in cells expressing pro-inflammatory and senescent phenotypes. An enrichment of B cells in the cases (p = 5.8 × 10−6) raises the possibility that some may have chronic endometritis, a disorder which predisposes to endometriosis. Conclusions We propose that characterization of endometrial tissues in ME will provide an effective screening tool for identifying endometriosis in patients with chronic symptoms suggestive of this disorder. This constitutes a major advance, since delayed diagnosis for many years is a major clinical problem in the evaluation of these patients. Comprehensive analysis of ME is expected to lead to new diagnostic and therapeutic approaches to endometriosis and other associated reproductive disorders such as female infertility.
Members of the mammalian Vestigial-like (VGLL) family of transcriptional cofactors activate genes in response to a wide variety of environmental cues. Recently, VGLL proteins have been proposed to regulate key signaling networks involved in cancer development and progression. However, the biological and clinical significance of VGLL dysregulation in human breast cancer pathogenesis remains unknown. Here, we report that diminished VGLL4 expression, but not VGLL1-3, correlated with both shorter relapse-free survival and shorter disease-specific survival of cancer patients with different molecular subtypes of breast cancer. Additionally, we further demonstrate that overexpression of VGLL4 reduces breast cancer cell proliferation, migration, intravasation/extravasation potential, favors cell death, and suppresses tumor growth in vivo. Mechanistically, VGLL4 negatively regulates the TEAD1-YAP1 transcriptional complex and exerts its growth inhibitory control through its evolutionary conserved TDU2 domain at its C-terminus. The results suggest that VGLL4 is a candidate tumor suppressor gene which acts by selectively antagonizing YAP-dependent tumor growth. VGLL4 may be a promising therapeutic target in breast cancer.
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