Ovarian cancer relies on the PDGFRβ–fibronectin axis for tumorsphere formation and metastatic spread

Abstract

High‐grade serous ovarian cancer (HGSOC) is the deadliest gynecological malignancy. The most common form of metastatic spread of HGSOC is transcoelomic dissemination. In this process, detached cells from the primary tumor aggregate as tumorspheres and promote the accumulation of peritoneal ascites. This represents an early event in HGSOC development and is indicative of poor prognosis. In this study, based on tumorspheres isolated from ascitic liquid samples from HGSOC patients, ovarian cancer spheroid 3D cultures, and in vivo models, we describe a key signal for tumorsphere formation in HGSOC. We report that platelet‐derived growth factor receptor beta (PDGFRβ) is essential for fibronectin‐mediated cell clustering of ovarian cancer cells into tumorspheres. This effect is mediated by the kinase NUAK family SNF1‐like kinase 1 (NUAK1) and blocked by PDGFRβ pharmacological or genetic inhibition. In the absence of PDGFRβ, ovarian cancer cells can be provided with fibronectin by cancer‐associated fibroblasts to generate chimeric spheroids. This work provides new insights that uncover potential targets to prevent peritoneal dissemination, the main cause of advanced disease in HGSOC patients.

Shaping Oncogenic Microenvironments: Contribution of Fibronectin

“…A compelling illustration is found in high-grade serous ovarian cancer (HGSOC), where metastasis to the abdominal space occurs through the formation of tumor cell aggregates that contain CAFs, and FN expressed by CAFs plays a crucial role in the aggregation process. Importantly, FN expression was dependent on PDGFR-β ( Gendrau-Sanclemente et al, 2023 ). On the other hand, it has been described that TG2 and cross-linked FN within extracellular vesicles (EVs) produced by metastatic breast cancer cells, determines the formation of the metastatic niche in lungs ( Shinde et al, 2020 ).…”