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000289227 1001_ $$00000-0003-0684-1380$$aFan, Guangjian$$b0
000289227 245__ $$aTSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.
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000289227 520__ $$aCancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.
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000289227 7001_ $$aYu, Bo$$b1
000289227 7001_ $$00000-0001-9418-4362$$aTang, Lei$$b2
000289227 7001_ $$aZhu, Rongxuan$$b3
000289227 7001_ $$00000-0001-6543-991X$$aChen, Jianhua$$b4
000289227 7001_ $$aZhu, Ying$$b5
000289227 7001_ $$00000-0002-2394-0877$$aHuang, He$$b6
000289227 7001_ $$aZhou, Liying$$b7
000289227 7001_ $$aLiu, Jun$$b8
000289227 7001_ $$aWang, Wei$$b9
000289227 7001_ $$aTao, Zhonghua$$b10
000289227 7001_ $$00000-0002-3715-6979$$aZhang, Fengchun$$b11
000289227 7001_ $$00009-0002-6991-5519$$aYu, Siwei$$b12
000289227 7001_ $$aLu, Xiaoqing$$b13
000289227 7001_ $$aCao, Yuan$$b14
000289227 7001_ $$00000-0001-8033-2387$$aDu, Shaoqian$$b15
000289227 7001_ $$aLi, Huihui$$b16
000289227 7001_ $$00000-0001-7970-4163$$aLi, Junjian$$b17
000289227 7001_ $$aZhang, Jian$$b18
000289227 7001_ $$00000-0002-9528-0580$$aRen, He$$b19
000289227 7001_ $$00000-0002-2292-7064$$aGires, Olivier$$b20
000289227 7001_ $$0P:(DE-He78)76aeb2431f7458c9261e69c5420390c6$$aLiu, Haikun$$b21$$udkfz
000289227 7001_ $$00000-0002-5122-2418$$aWang, Xin$$b22
000289227 7001_ $$00000-0002-2263-128X$$aQin, Jun$$b23
000289227 7001_ $$00000-0003-3481-6940$$aWang, Hongxia$$b24
000289227 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.adj5705$$gVol. 16, no. 741, p. eadj5705$$n741$$peadj5705$$tScience translational medicine$$v16$$x1946-6234$$y2024
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