ITGA7 loss drives the differentiation of adipose-derived mesenchymal stem cells to cancer-associated fibroblasts.

ABSTRACT

Cancer-associated fibroblasts (CAFs) represent a major cellular component of the tumor (pre-)metastatic niche and play an essential role in omental dissemination of ovarian cancer. The omentum is rich in adipose, and adipose-derived mesenchymal stem cells (ADSCs) have been identified as a source of CAFs. However, the molecular events driving the phenotype shift of ADSCs remain largely unexplored. In this research, we focus on integrins, transmembrane receptors that have been widely involved in cellular plasticity. We found that integrin α7 (ITGA7) was the only member of the integrin family that positively correlated with both overall survival and progression-free survival in ovarian cancer through GEPIA2. The immunohistochemistry signal of ITGA7 was apparent in the tumor stroma, and a lower omental ITGA7 level was associated with metastasis. Primary ADSCs were isolated from the omentum of patients with ovarian cancer and identified by cellular morphology, biomarkers, and multilineage differentiation. The conditional medium of ovarian cancer cells induced ITGA7 expression decrease and phenotypic changes in ADSCs. Downregulation of ITGA7 in primary omental ADSCs led to decrease in stemness properties and emerge of characteristic morphology and biomarkers of CAFs. Moreover, the conditioned medium of ADSCs with ITGA7 depletion exhibited enhanced abilities to improve the migration and invasion of ovarian cancer cells in vitro. Overall, these findings indicate that loss of ITGA7 may induce the differentiation of ADSCs to CAFs that contribute to a tumor-supportive niche.