Membrane-bound ICAM-1 contributes to the onset of proinvasive tumor stroma by controlling acto-myosin contractility in carcinoma-associated fibroblasts.

Stephanie Bonan,Eloise Grasset,Guerrino Meneguzzi,Thomas Bertero,Sanya-Eduarda Kuzet,Isabelle Bourget,Bernard Mari,Nicolas Nottet,Jean Albrengues,Cedric Gaggioli

doi:10.18632/oncotarget.13610

Abstract

Acto-myosin contractility in carcinoma-associated fibroblasts leads to assembly of the tumor extracellular matrix. The pro-inflammatory cytokine LIF governs fibroblast activation in cancer by regulating the myosin light chain 2 activity. So far, however, how LIF mediates cytoskeleton contractility remains unknown. Using phenotypic screening assays based on knock-down of LIF-dependent genes in fibroblasts, we identified the glycoprotein ICAM-1 as a crucial regulator of stroma fibroblast proinvasive matrix remodeling. We demonstrate that the membrane-bound ICAM-1 isoform is necessary and sufficient to promote inflammation-dependent extracellular matrix contraction, which favors cancer cell invasion. Indeed, ICAM-1 mediates generation of acto-myosin contractility downstream of the Src kinases in stromal fibroblasts. Moreover, acto-myosin contractility regulates ICAM-1 expression by establishing a positive feedback signaling. Thus, targeting stromal ICAM-1 might constitute a possible therapeutic mean to counteract tumor cell invasion and dissemination.

Highlights

Carcinoma-associated fibroblasts (CAF) are the most representative non-cancerous cell population of the tumor stroma
Using organotypic cell cultures submitted to threedimensional collagen-rich contraction assays after RNAimediated knock down of Leukemia Inhibitory Factor (LIF)-responsive genes, we show that membrane-bound Intercellular Adhesion Molecule 1 (ICAM-1) triggers tumorigenic ECM remodeling in CAF and in fibroblasts undergoing activation by tumor cells
We assessed whether such a LIF-dependent gene signature is shared by the CAF isolated from tissue biopsies of patients with head and neck, lung or breast carcinomas

Summary

Introduction

Carcinoma-associated fibroblasts (CAF) are the most representative non-cancerous cell population of the tumor stroma. Secretion of inflammatory molecules, including chemokines of the IL6 family, triggers a proinvasive fibroblast activation. In such context, we have demonstrated the crucial role that Leukemia Inhibitory Factor (LIF) plays in the proinvasive ECM remodeling by inducing acto-myosin contractility in fibroblasts [9]. In activated fibroblasts and CAF, constitutive activation and crosstalk of these two signaling pathways lead to the generation of fibrotic and tumorigenic cancer-associated ECM [10]. The LIF-dependent genes that mediate the crosstalk between inflammation and acto-myosin contractility in fibroblast remain to be identified

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Conclusion