Substratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1

Abstract

The Wnt/β-catenin pathway controls a variety of cellular behaviors, aberrant activation of which are associated with tumor progression in several types of cancer. The same cellular behaviors are also affected by the mechanical properties of the extracellular matrix (ECM) substratum, which induces signaling through integrins and integrin-linked kinase (ILK). Here, we examined the role of substratum stiffness in the regulation of cell proliferation downstream of Wnt3a. We found that treatment with Wnt3a increased proliferation of cells cultured on stiff substrata, with compliances characteristic of breast tumors, but not of cells on soft substrata, with compliances comparable to that of normal mammary tissue. Depleting ILK rendered cells unresponsive to Wnt3a on both substrata. Ectopic expression of ILK permitted Wnt3a to induce proliferation of cells on both microenvironments, although proliferation on soft substrata remained lower than that on stiff substrata. We further showed that ILK regulates expression of the Wnt receptor frizzled-1 (), suggesting the presence of a positive feedback loop between Wnt3a, ILK and Fzd1. These findings suggest that tissue mechanics regulates the cellular response to Wnt under physiological and pathological microenvironmental conditions.This article has an associated First Person interview with the first author of the paper.

Integrin-linked kinase tunes cell–cell and cell-matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGFβ1

“…We previously found that stably depleting ILK using short hairpin RNA (shRNA) leads to a striking change in the morphology of NMuMG mouse mammary epithelial cells ( Figure 1, A and B ) ( Han et al. , 2018 ).…”

“…, 2010 ). Given that stiff microenvironments up-regulate the expression of ILK ( Han et al. , 2018 ), it is possible that stiff matrices prime cells to undergo EMT through ILK-mediated signaling through Snail.…”

“…, 2003 ). Conversely, we recently found that depleting ILK abolishes the ability of cells to change their morphology in response to ECM stiffness—mammary epithelial cells that normally spread out on stiff substrata exhibit a rounded morphology when ILK is down-regulated ( Han et al. , 2018 ).…”

Overexpression of FZD1 is Associated with a Good Prognosis and Resistance of Sunitinib in Clear Cell Renal Cell Carcinoma

“…A previous research uncovered sunitinib's actions on the brain tumor microenvironment impedes brain tumor progression 21. FZD1 could also get involved in cellular microenvironment in the regulation of cell proliferation 22. There was a report that FZD1 expression in the tumor microenvironment had a gradient effect may modulate colon cancer progression and dissemination, representing a new therapeutic target for patients with colon cancer 23.…”

Physical and mechanical cues affecting biomaterial-mediated plasmid DNA delivery: insights into non-viral delivery systems

“…In general, in spite of several studies assessing the biological effect of substrate stiffness [ 194 , 195 , 209 – 216 ], cytoskeletal trafficking/structural changes in cells encapsulated in biomaterials of different stiffness has been scarcely investigated, with no consensus having been reached as yet. Further research on this direction is limited by the fact that biomaterial stiffness influences several other different processes, including biomaterial degradation rate, cellular infiltration, migration and proliferation rate.…”