Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling  

作　　者：Hee Ja Kim Kyungwon Yang Kiyoon Kim Ye‐Ji Lee Sieun Lee Sung Yong Ahn Young‐Ho Ahn Jihee Lee Kang 

机构地区：[1]Department of Physiology,College of Medicine,Ewha Womans University,Seoul,07804,Korea [2]Inflammation-Cancer Microenvironment Research Center,College of Medicine,Ewha Womans University,Seoul,07804,Korea [3]Department of Molecular Medicine,College of Medicine,Ewha Womans University,Seoul,07804,Korea

出　　处：《Cellular & Molecular Immunology》2022年第12期1373-1391,共19页中国免疫学杂志（英文版）

基　　金：supported by National Research Foundation of Korea (NRF) grants (2020R1A5A2019210 and 2020R1A2B5B02001686) funded by the Korean Ministry of Science and ICT.

摘　　要：The interplay between apoptotic cancer cells and the tumor microenvironment modulates cancer progression and metastasis.Cancer-associated fibroblasts(CAFs)play a crucial role in promoting these events through paracrine communication.Here,we demonstrate that conditioned medium(CM)from lung CAFs exposed to apoptotic cancer cells suppresses TGF-β1-induced migration and invasion of cancer cells and CAFs.Direct exposure of CAFs to apoptotic 344SQ cells(ApoSQ)inhibited CAF migration and invasion and the expression of CAF activation markers.Enhanced secretion of Wnt‐induced signaling protein 1(WISP-1)by CAFs exposed to ApoSQ was required for these antimigratory and anti-invasive effects.Pharmacological inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the antimigratory and anti-invasive effects.Enhanced expression of the Notch ligand delta-like protein 1 on the surface of ultraviolet-irradiated apoptotic lung cancer cells triggered Notch1-WISP-1 signaling.Phosphatidylserine receptor brain-specific angiogenesis inhibitor 1(BAI1)-Rac1 signaling,which facilitated efferocytosis by CAFs,participated in crosstalk with Notch1 signaling for optimal production of WISP-1.In addition,a single injection of ApoSQ enhanced WISP-1 production,suppressed the expression of CAF activation markers in isolated Thy1^(+)CAFs,and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling.Treatment with CM from CAFs exposed to ApoSQ suppressed tumor growth and lung metastasis,whereas treatment with WISP-1-immunodepleted CM from CAFs exposed to ApoSQ reversed the antitumorigenic and antimetastatic effects.Therefore,treatment with CM from CAFs exposed to apoptotic lung cancer cells could be therapeutically applied to suppress CAF activation,thereby preventing cancer progression and metastasis.

关 键 词：CAFs Apoptotic lung cancer cells NOTCH1 WISP-1 EFFEROCYTOSIS Migration Invasion Metastasis 

分 类 号：R734.2[医药卫生—肿瘤]