Extracellular Signaling Molecules from Adipose-Derived Stem Cells and Ovarian Cancer Cells Induce a Hybrid Epithelial-Mesenchymal Phenotype in a Bidirectional Interaction

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Simao, Vinicius Augusto ; Floriano, Juliana Ferreira ; Cesario, Roberta Carvalho ; Tonon, Karolina da Silva ; de Oliveira, Larissa Ragozo Cardoso ; Delella, Flavia Karina ; Almeida, Fausto ; dos Santos, Lucilene Delazari ; Seiva, Fabio Rodrigues Ferreira ; Zuccari, Debora Aparecida Pires de Campos ; Ribeiro-Paes, Joao Tadeu ; Reiter, Russel J. ; Chuffa, Luiz Gustavo de Almeida

• Document type: Journal article
• Source: CELLS; v. 14, n. 5, p. 33-pg., 2025-03-01.

Abstract

Ovarian cancer (OC) is characterized by high mortality rates due to late diagnosis, recurrence, and metastasis. Here, we show that extracellular signaling molecules secreted by adipose-derived mesenchymal stem cells (ASCs) and OC cells-either in the conditioned medium (CM) or within small extracellular vesicles (sEVs)-modulate cellular responses and drive OC progression. ASC-derived sEVs and CM secretome promoted OC cell colony formation, invasion, and migration while upregulating tumor-associated signaling pathways, including TGF beta/Smad, p38MAPK/ERK1/2, Wnt/beta-catenin, and MMP-9. Additionally, OC-derived sEVs and CM induced a pro-tumorigenic phenotype in ASCs, enhancing their invasiveness and expression of tumor-associated factors. Notably, both ASCs and OC cells exhibited increased expression of E-cadherin and Snail/Slug proteins, key markers of epithelial/mesenchymal hybrid phenotype, enhancing cellular plasticity and metastatic potential. We also demonstrated that these cellular features are, at least in part, due to the presence of tumor-supportive molecules such as TNF-alpha, Tenascin-C, MMP-2, and SDF-1 alpha in the CM secretome of ASCs and OC cells. In silico analyses linked these molecular changes to poor prognostic outcomes in OC patients. These findings highlight the critical role of sEVs and tumor/stem cell-derived secretome in OC progression through bidirectional interactions that impact cellular behavior and phenotypic transitions. We suggest that targeting EV-mediated communication could improve therapeutic strategies and patient outcomes. (AU)

• FAPESP's process: 21/02229-1 - Human Adipose-derived Mesenchymal Stem Cells and Melatonin: In vitro and In vivo Therapeutic Potential in Ovarian Cancer
• Grantee: Vinicius Augusto Simao
• Support Opportunities: Scholarships in Brazil - Post-Doctoral