Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.</jats:p>

The metabolic roots of senescence: mechanisms and opportunities for intervention

“…Recent findings show that lysosomal permeability increases in senescent cells. This increase results in the previously observed loss of lysosomal acidity 141,142 , but also elevates cytosolic acidification 143 . To combat this increase, senescent cells upregulate glutaminolysis by increasing glutaminase 1 (GLS1) expression, which increases ammonia production and neutralizes the cytosolic acidity 143 .…”

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

“…MIT was delivered via i.p. injection biweekly starting from the beginning of the 3rd week, with a total of three 2-week cycles throughout the whole regimen as reported previously 16,17 . PCC1 was delivered via i.p.…”

“…We employed a primary normal human prostate stromal cell line, PSC27, as a cell-based model for this purpose. Composed mainly of fibroblasts but with a minor percentage of non-fibroblast cell lineages including endothelial cells and smooth muscle cells, PSC27 is a primary cell line per se and develops a typical SASP after exposure to stressors such as genotoxic chemotherapy or ionizing radiation [14][15][16][17] . We treated these cells with a pre-optimized sublethal dose of bleomycin (50 μg ml −1 ) and observed increased senescence-associated β-galactosidase (SA-β-Gal) staining, decreased 5-bromodeoxyuridine incorporation and elevated DNA-damage repair (DDR) foci 7-10 d after (Supplementary Fig.…”

The Regulatory Effect of SIRT1 on Extracellular Microenvironment Remodeling

“…In senescent stromal cells, SIRT1-loss also causes impairment of lysosomes acidification and protein degradation. That is why senescent cells presumably prefer to release small extracellular vesicles into the tumor microenvironment, which enhances the aggressiveness and drug resistance of recipient cancer cells mediated by ATP binding cassette subfamily B member 4 (ABCB4) [115].…”