title: Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts.
abstract: Increased deposition of collagen in extracellular matrix (ECM) leads to increased tissue stiffness and occurs in breast tumors. When present, this increases tumor invasion and metastasis. Precisely how this deposition is regulated and maintained in tumors is unclear. Much has been learnt about mechanical signal transduction in cells, but transcriptional responses and the pathophysiological consequences are just becoming appreciated. Here, we show that the SNAIL1 (also known as SNAI1) protein level increases and accumulates in nuclei of breast tumor cells and cancer-associated fibroblasts (CAFs) following exposure to stiff ECM in culture and in vivo SNAIL1 is required for the fibrogenic response of CAFs when exposed to a stiff matrix. ECM stiffness induces ROCK activity, which stabilizes SNAIL1 protein indirectly by increasing intracellular tension, integrin clustering and integrin signaling to ERK2 (also known as MAPK1). Increased ERK2 activity leads to nuclear accumulation of SNAIL1, and, thus, avoidance of cytosolic proteasome degradation. SNAIL1 also influences the level and activity of YAP1 in CAFs exposed to a stiff matrix. This work describes a mechanism whereby increased tumor fibrosis can perpetuate activation of CAFs to sustain tumor fibrosis and promote tumor metastasis through regulation of SNAIL1 protein level and activity.
authors.affiliation: ICCE Institute, Washington University, St Louis, MO 63110, USA Department of Medicine, Washington University, St Louis, MO 63110, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: ICCE Institute, Washington University, St Louis, MO 63110, USA Biochemistry, Washington University, St Louis, MO 63110, USA.
authors.forename: Whitney R
authors.initials: WR
authors.lastname: Grither
authors.affiliation: ICCE Institute, Washington University, St Louis, MO 63110, USA Cell Biology and Physiology, Washington University, St Louis, MO 63110, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Van Hove
authors.affiliation: ICCE Institute, Washington University, St Louis, MO 63110, USA Cell Biology and Physiology, Washington University, St Louis, MO 63110, USA.
authors.forename: Hirak
authors.initials: H
authors.lastname: Biswas
authors.affiliation: Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Ponik
authors.affiliation: Laboratory for Optical and Computational Imaging, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: ICCE Institute, Washington University, St Louis, MO 63110, USA Department of Medicine, Washington University, St Louis, MO 63110, USA Cell Biology and Physiology, Washington University, St Louis, MO 63110, USA glongmore@wustl.edu.
authors.forename: Gregory D
authors.identifier: 0000-0001-7568-8151
authors.initials: GD
authors.lastname: Longmore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D054460:rho-Associated Kinases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D003094:Collagen; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
keywords: Extracellular matrix; Fibrosis; Mechanotransduction; SNAIL1