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Small Extracellular Vesicles from Hypoxic Triple-Negative Breast Cancer Cells induce Oxygen-dependent Cell Invasion

ABSTRACT: Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors, is often related to increased extracellular vesicle (EV) secretion and favors cell invasion, which is a crucial step for metastasis. Cell invasion is a complex process in which cell morphology is altered due to F-actin cytoskeleton polarization and the establishment of dynamic focal adhesion spots, which coupled with ECM remodeling enables cells to migrate through tissues seeking a new developmental niche. In our in-depth investigation over the invasive properties triggered by TNBC-derived hypoxic small EVs (SEVh) in vitro, we analyzed the morphological, phenotypical and proteomic distinctions promoted by hypoxia and/or SEVh signaling in TNBC cells. SEVh was fully characterized and showed a distinct proteome and abundance profile from its normoxic counterparts. SEVh promotes invasive behaviors exclusively in normoxia, including pro-migratory morphology, invadopodia development, ECM degradation and gelatinase secretion, which indicates the importance of SEVh response on hypoxic settings in tumor progression. In hypoxia, SEVh was responsible for proteolytic and catabolic pathway inducement, interfering with integrin availability and gelatinase expression. Protein profiling of SEVh-treated, normoxic cells indicate a baseline favoring of metabolic processes and cell cycle, modulating cell health away from apoptotic pathways that are enriched in hypoxia. Overall, our results demonstrate the importance of hypoxic signaling via SEV in a tumoral setting for the early establishment of metastasis.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Bianca Cruz Pachane

LAB HEAD: Wanessa Fernanda Altei

PROVIDER: PXD035244 | Pride | 2022-11-01

REPOSITORIES: Pride

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			Action	DRS
	20220107_Branco_1_Slot1-1_1_567.d.zip	Other
	20220107_Branco_2_Slot1-1_1_571.d.zip	Other
	20220107_Branco_3_Slot1-1_1_575.d.zip	Other
	20220107_Branco_4_Slot1-1_1_579.d.zip	Other
	20220107_Branco_5_Slot1-1_1_583.d.zip	Other

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Project description:The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic ATP production, an event with consequences for both cell bioenergetics and cell fate. This response is regulated at the transcriptional level by HIF-1-dependent transcriptional upregulation of all ten glycolytic enzymes. However, this response alone does not account for the levels of ATP produced in hypoxia. Here, we investigated additional mechanisms of regulating glycolysis in hypoxia. We found that both intestinal epithelial cells treated with inhibitors of transcription and translation and human platelets (which lack nuclei) maintained the capacity for hypoxia-induced glycolysis, suggesting the involvement of a non-transcriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. Mass spectrometric analysis of the interactome of immunoprecipitated rate-limiting glycolytic enzymes identified hypoxia-sensitive complexes comprising multiple glycolytic enzymes and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of glycolytic complexes, though not dependent upon transcription, occurs via a HIF-1?-dependent mechanism, suggesting that HIF-1? may play a moonlighting role in the formation / maintenance of glycolytic complexes. Furthermore, we provide evidence for the presence of HIF-1? in cytosolic fractions of hypoxic cells which physically associated with the glucose transporter GLUT1 and the glycolytic enzyme PFKP in a hypoxia-sensitive manner. In conclusion, we hypothesize that HIF-1? plays a role in initiation and/or maintenance of glycolytic complexes in intestinal epithelial cells under hypoxic conditions in a manner which optimizes catalytic efficiency of the pathway by facilitating substrate channeling of glycolytic intermediates between sequential pathway enzymes. In hypoxia, cells undergo a metabolic switch to increased glycolysis. This has important implications for cell behavior, phenotype, and fate in both healthy and cancerous cells. Here we describe a mechanism by which HIF-1, in addition to increasing glycolytic enzyme expression, promotes glycolysis via the formation of a metabolic complex.

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Small Extracellular Vesicles from Hypoxic Triple-Negative Breast Cancer Cells induce Oxygen-dependent Cell Invasion

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