title: Twist1 is a key regulator of cancer-associated fibroblasts.
abstract: Cancer-associated fibroblasts (CAF) are key contributors to malignant progression, but their critical regulators remain largely unknown. In this study, we examined the role of Twist1, a central regulator of epithelial-mesenchymal transition in carcinoma cells, in the transdifferentiation of normal quiescent fibroblasts to CAF and we defined its upstream controls and downstream effectors. Primary human gastric fibroblast and CAF cultures were established from gastrectomy specimens and validated as nontumor cells by somatic mutation analyses. In these cultures, exposure to the proinflammatory cytokine IL6 commonly expressed in tumors was sufficient to induce Twist1 expression in normal fibroblasts and transdifferentiate them into CAFs via STAT3 phosphorylation. In xenograft models, tumor infiltration of Twist1-expressing CAFs was enhanced strongly by ectopic IL6 expression in gastric or breast cancer cells. We found that Twist1 expression was necessary and sufficient for CAF transdifferentiation. Enforced expression of Twist1 in normal fibroblasts was also sufficient to drive CAF marker expression and malignant character in gastric cancer cells both in vitro and in vivo. Conversely, silencing the expression of Twist1 in CAFs abrogated their tumor-promoting properties. Downstream of Twist1, we defined the chemokine CXCL12 as a transcriptional target. Clinically, CXCL12 and Twist1 expression were correlated in CAFs present in gastric tumor specimens. Finally, ectopic expression of Twist1 in normal fibroblasts suppressed premature senescence, whereas Twist1 attenuation accelerated senescence in CAFs. Our findings define Twist1 as a compelling target to deprogram the tumor-supporting features of the cancer microenvironment.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Keun-Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Yeo
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Chang Ohk
authors.initials: CO
authors.lastname: Sung
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea. platoshkim@daum.net.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508600:IL6 protein, human; D015850:Interleukin-6; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1