miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts

Author(s):Show less -

Xue, Bin ^[1] ; Chuang, Chen-Hua ^[2] ; Prosser, Haydn M. ^{[3, 4]} ; Fuziwara, Cesar Seigi ^{[5, 1]} ; Chan, Claudia ^[1] ; Sahasrabudhe, Neil ^[1] ; Kuhn, Maximilian ^[1] ; Wu, Yalei ^[6] ; Chen, Jingqi ^[1] ; Biton, Anne ^{[7, 8]} ; Chen, Caifu ^[6] ; Wilkinson, John Erby ^[9] ; McManus, Michael T. ^[10] ; Bradley, Allan ^{[3, 4]} ; Winslow, Monte M. ^[2] ; Su, Bo ^[11] ; He, Lin ^[1]

Affiliation:Show less -

^[1] Univ Calif Berkeley, Mol & Cell Biol Dept, Div Cellular & Dev Biol, Berkeley, CA 94705 - USA

^[2] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 - USA

^[3] Wellcome Trust Sanger Inst, Cambridge CB10 1SA - England

^[4] Univ Cambridge, Cambridge Inst Therapeut Immunol & Infect Dis, Dept Med, Cambridge CB2 0AW - England

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, BR-05508000 Sao Paulo - Brazil

^[6] Thermo Fisher Sci, San Francisco, CA 94080 - USA

^[7] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94705 - USA

^[8] CNRS, Inst Pasteur, Dept Computat Biol, Bioinformat & Biostat, USR 3756, Paris 01 - France

^[9] Univ Michigan, Med Sch, Dept Pathol, Ann Arbor, MI 48109 - USA

^[10] Univ Calif San Francisco, WM Keck Ctr Noncoding RNAs, Diabet Ctr, Dept Microbiol & Immunol, San Francisco, CA 94143 - USA

^[11] Tongji Univ, Sch Med, Shanghai Pulm Hosp, Cent Lab, Shanghai 200433 - Peoples R China

• Document type: Journal article
• Source: GENES & DEVELOPMENT; v. 35, n. 15-16, p. 1109+, AUG 1 2021.
• Web of Science Citations: 0

Abstract

Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the Kras(LSL-G12D/+); Trp53(flox/flox) lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential. (AU)

• FAPESP's process: 19/17282-5 - Transcriptional and post-transcriptional control in aggressive cancer and metastasis
• Grantee: Cesar Seigi Fuziwara
• Support Opportunities: Research Grants - Young Investigators Grants