期刊
CANCER RESEARCH
卷 80, 期 16, 页码 3383-3398出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-0506
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资金
- National Key Research and Development Program of China [2016YFC1302400, 2019YFC2002801]
- National Natural Science Foundation of China [81472709, 31671425, 31871380]
- Strategic Priority Research Program of Chinese Academy of Sciences [XDB39010500]
- CAS Key Laboratory of Tissue Microenvironment and Tumor of Chinese Academy of Sciences [201506, 201706]
- National 1000 Young Talents Research Program of China
- Anti-Aging Collaborative Program of SIBS and BY-HEALTH [C01201911260006]
- University and Locality Collaborative Development Program of Yantai [2019XDRHXMRC08]
- US Department of Defense (DoD) Prostate Cancer Research Program (Idea Development Award) [PC111703]
- National Science and Technology Major Project of China [2019ZX09732002-14]
- CRUK [A12011]
- Breast Cancer Now [2012MayPR070, 2012NovPhD016]
- Medical Research Council of the United Kingdom [MR/N012097/1]
- Imperial ECMC
- NIHR Imperial BRC
- MRC [MR/N012097/1] Funding Source: UKRI
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, which is implicated in age-related pathologies including cancer. Here, we report that senescent cells actively synthesize and release small extracellular vesicles (sEV) 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 pathologic activities of senescent cells and provides a potent avenue to circumvent advanced human malignancies by cotargeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells. Significance: Senescent stromal cells produce a large number of sEVs to promote cancer resistance in therapeutic settings, a process driven by SIRT1 decline in stromal cells and ABCB4 augmentation in cancer cells.
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