Abstract
Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg’s effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.
Highlights
Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases)
We considered that the stroma could be a key actor of Mesenchymal HGSOC aggressiveness, and we addressed the role of stiffness in this specific molecular subtype of ovarian cancer
To address this question in vivo, we benefited from three distinct patient-derived xenograft (PDX) mouse models, two (OV26 and OV21) derived from two Mesenchymal HGSOC patients and one (OV33) from NonMesenchymal HGSOC patient
Summary
Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). By combining transcriptomic data with miR-141/200a expression level, we identified transcriptomic signatures that differentiate Mesenchymal versus Non-Mesenchymal HGSOC This signature is mainly composed of stromal genes encoding extracellular matrix (ECM) proteins and ECM remodeling e nzymes[29,31,43]. Mesenchymal tumors are characterized by a high content of Cancer-Associated Fibroblasts and accumulation of ECM proteins, such as collagen and fibronectin[27,28,29,44,45,46,47,48,49,50] In this context, we considered that the stroma could be a key actor of Mesenchymal HGSOC aggressiveness, and we addressed the role of stiffness in this specific molecular subtype of ovarian cancer. In breast cancer, tumor stiffening induces a metabolic switch in cancer and stromal cells to support malignancy[70]
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