Integrated molecular profiling of patient‐derived ovarian cancer models identifies clinically relevant signatures and tumor vulnerabilities. Issue 2 (14th March 2022) - Lupia, Michela
Abstract: High‐grade serous ovarian carcinoma (HGSOC) is a highly aggressive and intractable neoplasm, mainly because of its rapid dissemination into the abdominal cavity, a process that is favored by tumor‐associated peritoneal ascites. The precise molecular alterations involved in HGSOC onset and progression remain largely unknown due to the high biological and genetic heterogeneity of this tumor. We established a set of different tumor samples (termed the As11‐set) derived from a single HGSOC patient, consisting of peritoneal ascites, primary tumor cells, ovarian cancer stem cells (OCSC) and serially propagated tumor xenografts. The As11‐set was subjected to an integrated RNA‐seq and DNA‐seq analysis which unveiled molecular alterations that marked the different types of samples. Our profiling strategy yielded a panel of signatures relevant in HGSOC and in OCSC biology. When such signatures were used to interrogate the TCGA dataset from HGSOC patients, they exhibited prognostic and predictive power. The molecular alterations also identified potential vulnerabilities associated with OCSC, which were then tested functionally in stemness‐related assays. As a proof of concept, we defined PI3K signaling as a novel druggable target in OCSC. Abstract : What's new? High‐grade serous ovarian carcinoma (HGSOC) is aggressive and frequently fatal, and its high degree of heterogeneity has made it difficult to characterize the molecular changes that promote its progression. Here, the authors collected a set of samples from a single patient consisting of multiple cell types representing different steps in tumor progression. They conducted DNA and RNA sequencing to create a panel of molecular signatures that distinguished the different cell types. This panel not only showed prognostic value, it also revealed the PI3K signaling pathway as a potential druggable target in ovarian cancer stem cells.