Biology subjects

Drapkin, R.

Publications and source records attributed to Drapkin, R..

3 recordsLinked to original sources

bioRxiv2018

Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer

Historically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj = 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P < 2.2 x 10-16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.

cancer biology↗

bioRxiv2018

Replication stress induced by CCNE1 overexpression creates a dependency on XRCC2 at the replication fork

Across multiple cancer types, genome instability has been linked to aberrant over-expression of CCNE1 due to premature cell cycle entry and replication stress. Using a gain-of-function screen, we found that XRCC2 cooperates with CCNE1 in the neoplastic transformation of TP53 mutant cells. A pan-cancer analysis of TCGA data revealed a striking correlation between CCNE1 and XRCC2 expression and knockdown of XRCC2 in Cyclin E1 overexpressing cell lines is synthetic lethal. Immunopurification of XRCC2 showed that it interacts with the Minichromosome Maintenance Complex Component 7 (MCM7) protein. This interaction appears to be critical for protecting replication forks as knockdown of XRCC2 leads to a strong increase in MCM7 ubiquitination with concomitant decrease in MCM7 protein levels, and reduced replication fork speed. Importantly, Overexpression of MCM7 rescues the effect of XRCC2 knockdown. Our data describe a new dependency of Cyclin E1 overexpressing tumors on factors that stabilize the replication fork.

molecular biology↗

bioRxiv2018

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

Most high-grade serous ovarian carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). FT secretory cells become malignant by accumulating genomic aberrations over 6-7 years before seeding the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical surface of STIC lesions and contributed to ovarian colonization by upregulating integrin and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study metastasis to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in L1CAM-dependent manner.\n\nThe authors have declared that no conflict of interest exists\n\nList of abbreviations

cancer biology↗