Role of TRPC1 channels in pressure-mediated activation of murine pancreatic stellate cells.
The tumor environment contributes importantly to tumor cell behavior and cancer progression. Aside from biochemical constituents, physical factors of the environment also influence the tumor. Growing evidence suggests that mechanics [e.g., tumor (stroma) elasticity, tissue pressure] are critical players of cancer progression. Underlying mechanobiological mechanisms involve among others the regulation of focal adhesion molecules, cytoskeletal modifications, and mechanosensitive (MS) ion channels of cancer- and tumor-associated cells. After reviewing the current concepts of cancer mechanobiology, we will focus on the canonical transient receptor potential 1 (TRPC1) channel and its role in mechano-signaling in tumor-associated pancreatic stellate cells (PSCs). PSCs are key players of pancreatic fibrosis, especially in cases of pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by the formation of a dense fibrotic stroma (desmoplasia), primarily formed by activated PSCs. Desmoplasia contributes to high pancreatic tissue pressure, which in turn activates PSCs, thereby perpetuating matrix deposition. Here, we investigated the role of the putatively mechanosensitive TRPC1 channels in murine PSCs exposed to elevated ambient pressure. Pressurization leads to inhibition of mRNA expression of MS ion channels. Migration of PSCs representing a readout of their activation is enhanced in pressurized PSCs. Knockout of TRPC1 leads to an attenuated phenotype. While TRPC1-mediated calcium influx is increased in wild-type PSCs after pressure incubation, loss of TRPC1 abolishes this effect. Our findings provide mechanistic insight how pressure, an important factor of the PDAC environment, contributes to PSC activation. TRPC1-mediated activation could be a potential target to disrupt the positive feedback of PSC activation and PDAC progression.
Institute of Physiology II, University of Münster, Robert-Koch-Str. 27b, 48149, Munster, Germany.
Benedikt
B
Fels
Institute of Physiology II, University of Münster, Robert-Koch-Str. 27b, 48149, Munster, Germany. b_fels01@uni-muenster.de.|Novo Nordisk A/S, Smørmosevej 10-12, 2880, Bagsværd, Denmark. b_fels01@uni-muenster.de.
Nikolaj
N
Nielsen
Institute of Physiology II, University of Münster, Robert-Koch-Str. 27b, 48149, Munster, Germany.
Albrecht
A
Schwab
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D011312:Pressure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium
Mechanosensitive ion channels; PDAC; Pancreatic stellate cells; Pressure; TRPC1
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