Abstract IA06: Stromal regulation of metastasis
Authors: Lengyel Ernst , Eckert Mark , Romero Iris , Kenny Hilary 
Published: August 2018

Most patients with high-grade serous ovarian cancer (HGSOC) develop metastasis early and, while they are initially chemoresponsive, the existence of disseminated, solid tumors generally leads to the grim prognosis associated with the disease. Many studies of metastasis in HGSOC focus on the epithelial cancer cell and its genetic and epigenetic makeup, underestimating the contribution of the host microenvironment. The metastatic pattern of HGSOC is very different from other epithelial cancers (e.g., breast cancer), since metastasis is mostly limited to the mesothelial cell covered surfaces of the abdominal cavity or retroperitoneal lymph nodes. Even before they metastasize, ovarian cancer cells at the primary site use exosomes to prime the metastatic sites. In parallel, the stromal cells of the primary metastatic sites, generally the omentum and peritoneum, release cytokines that attract the cancer cells. Once the individual HGSOC cells or cell spheroids “land” on the omentum or peritoneum, an intensive bidirectional signaling ensues between the cancer cells and host fibroblasts, mesothelial cells, adipocytes, and immune cells. Mesothelial cells and macrophages initially fight the local invasion by blocking the attachment of cancer cells or recruiting various inflammatory cells to the site of micrometastasis, where the immune cells surround the metastasis. Subsequently, the cancer cells activate the dispersal of the mesothelial cells, attach to the sub-mesothelial basement membrane and reprogram fibroblasts. Within a short period of time, cancer cells transform normal fibroblasts within the ECM into cancer-associated fibroblasts (CAF). Eventually, most stromal cells become cancer associated stromal cells, releasing pro-proliferative and migratory cytokines. In addition, metabolic reprogramming takes place, involving reciprocal metabolic interactions between the cancer and stromal cells. The cancer cells are able to extract fatty acids, to be used as fuel, from cancer-associated adipocytes. Also, a hypoxic environment is produced. This advantages the cancer cells, since they readily adapt to a low-oxygen environment and hypoxia is known to impair the efficacy of chemotherapy. Ultimately, the metastatic site is taken over by the tumor organ. We will present data from our use of organotypic 3D cultures of the metastatic site and systematic metabolic and proteomic analysis of the interactions between stromal and cancer cells, which has informed our attempts to understand the complexities of HGSOC metastasis. Only an improved understanding of the biology of metastasis and the metabolic symbiosis within the tumor will allow the identification of novel targets that can be used to disrupt the metastatic process and impair the ability of HGSOC to recruit the stroma.

Citation Format: Ernst Lengyel, Mark Eckert, Iris Romero, Hilary Kenny. Stromal regulation of metastasis. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA06.