Integrated molecular profiling of patient‐derived ovarian cancer models identifies clinically relevant signatures and tumor vulnerabilities

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 stemnessrelated assays. As a proof of concept, we defined PI3K signaling as a novel druggable target in OCSC.

Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer

“…Nevertheless, the molecular and functional properties of OCSC have remained largely elusive due to different factors, one of the most prominent being the lack of clinically representative model systems. We have overcome this issue by relying on a series of patient-derived primary cultures, an approach that has recently revealed novel and unexpected players not only in OC per se but also in the OCSC subset [ 16 , 17 , 49 , 50 ]. Along this line, primary cultures unveiled MGP as a hallmark of OCSC and provided the rationale for subsequent functional studies.…”

Matrix Gla Protein acts as a driver of stemness and tumor initiation in ovarian cancer

“…Nevertheless, the molecular and functional properties of OCSC have remained largely elusive due to different factors, one of the most prominent being the lack of clinically representative model systems. We have overcome this issue by relying on a series of patient-derived primary cultures, an approach that has recently revealed novel and unexpected players not only in OC per se but also in the OCSC subset [16,[41][42][43]. Along this line, primary cultures unveiled MGP as a hallmark of OCSC and provided the rationale for subsequent functional studies.…”

Personalization of Therapy in High-Grade Serous Tubo-Ovarian Cancer—The Possibility or the Necessity?

“…It was dominated by genes regulating the inflammatory response, NF-κB activity, EGF signaling, and hypoxia. Finally, QT-C with genes involved in mesenchymallike and non-proliferating OCSCs-like cells [38]. It was noticed that the QT-A signature was predominant in the proliferative HGSTOC subtype, QT-B in the inflammatory subtype, and QT-C in the mesenchymal subtype, respectively [38].…”