Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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), which is 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 supported accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly altered the expression profile of recipient cancer cells and enhanced their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with agonist SRT2104 prevented development of cancer resistance by restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients were readily detectable by routine biotechniques, presenting an exploitable biomarker to monitor therapeutic efficacy and predict long-term outcome. Together, this study identifies a distinct mechanism supporting pathological activities of senescent cells and provides a potent 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.
Date Issued
2020-08-01
Date Acceptance
2020-04-29
Citation
Cancer Research, 2020, 80 (16), pp.3383-3398
ISSN
0008-5472
Publisher
American Association for Cancer Research
Start Page
3383
End Page
3398
Journal / Book Title
Cancer Research
Volume
80
Issue
16
Copyright Statement
©2020, American Association for Cancer Research.
Sponsor
Cancer Research UK
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Breast Cancer Care & Breast Cancer Now
Grant Number
12011
2012MayPR070
MR/N012097/1
2012NovemberPhD016
Subjects
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status
Published
Date Publish Online
2020-05-04