Small Extracellular Vesicles from Hypoxic Triple-Negative Breast Cancer Cells Induce Oxygen-Dependent Cell Invasion

Author(s)

Pachane, Bianca Cruz ; Caetano Nunes, Ana Carolina ; Cataldi, Thais Regiani ; Micocci, Kelli Cristina ; Moreira, Bianca Caruso ; Labate, Carlos Alberto ; Selistre-de-Araujo, Heloisa Sobreiro ; Altei, Wanessa Fernanda

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 20, p. 21-pg., 2022-10-01.

Abstract

Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors (TNBC), promotes extracellular vesicle (EV) secretion and favors cell invasion, a complex process in which cell morphology is altered, dynamic focal adhesion spots are created, and ECM is remodeled. Here, we investigated the invasive properties triggered by TNBC-derived hypoxic small EV (SEVh) in vitro in cells cultured under hypoxic (1% O-2) and normoxic (20% O-2) conditions, using phenotypical and proteomic approaches. SEVh characterization demonstrated increased protein abundance and diversity over normoxic SEV (SEVn), with enrichment in pro-invasive pathways. In normoxic cells, SEVh promotes invasive behavior through pro-migratory morphology, invadopodia development, ECM degradation, and matrix metalloprotease (MMP) secretion. The proteome profiling of 20% O-2-cultured cells exposed to SEVh determined enrichment in metabolic processes and cell cycles, modulating cell health to escape apoptotic pathways. In hypoxia, SEVh was responsible for proteolytic and catabolic pathway inducement, interfering with integrin availability and gelatinase expression. Overall, our results demonstrate the importance of hypoxic signaling via SEV in tumors for the early establishment of metastasis. (AU)

• FAPESP's process: 21/01983-4 - Influence of hypoxic extracellular vesicles in cell invasion and tumour microenvironment on Breast Cancer
• Grantee: Bianca Cruz Pachane
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/06198-8 - Functional study of acetylcholinesterase (AChE) and other enzymes of Atta Sexdens rubropilosa and their symbiotic fungus Leucoagaricus gongylophorus, their immobilization in electrode and search of specific inhibitors
• Grantee: Kelli Cristina Micocci
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/11437-7 - Integrin molecular mechanisms of action during tumor progression and metastasis development: an intercellular approach
• Grantee: Heloisa Sobreiro Selistre de Araújo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/05149-9 - Role of extracellular vesicle gelatinase in tumour cell invasion in normoxia and hypoxia
• Grantee: Bianca Cruz Pachane
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/17737-2 - Effects of low carbohydrate and high fat diet associated or not to resistant training on extracellular matrix remodeling and cardiac ventricular fibrosis in rats
• Grantee: Bianca Caruso Moreira
• Support Opportunities: Scholarships in Brazil - Master