Bonan Stephanie, Albrengues Jean, Grasset Eloise, Kuzet Sanya-Eduarda, Nottet Nicolas, Bourget Isabelle, Bertero Thomas, Mari Bernard, Meneguzzi Guerrino, Gaggioli Cedric
INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, F-06107, Nice, France.
Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, Sophia-Antipolis, France.
Oncotarget. 2017 Jan 3;8(1):1304-1320. doi: 10.18632/oncotarget.13610.
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.
癌相关成纤维细胞中的肌动球蛋白收缩性导致肿瘤细胞外基质的组装。促炎细胞因子白血病抑制因子（LIF）通过调节肌球蛋白轻链2的活性来控制癌症中纤维母细胞的激活。然而，迄今为止，LIF如何介导细胞骨架收缩性仍不清楚。通过基于敲除成纤维细胞中LIF依赖性基因的表型筛选试验，我们确定糖蛋白细胞间黏附分子-1（ICAM-1）是基质成纤维细胞促侵袭性基质重塑的关键调节因子。我们证明，膜结合的ICAM-1同种型对于促进炎症依赖性细胞外基质收缩是必要且充分的，这有利于癌细胞的侵袭。实际上，ICAM-1在基质成纤维细胞中介导Src激酶下游的肌动球蛋白收缩性的产生。此外，肌动球蛋白收缩性通过建立正反馈信号来调节ICAM-1的表达。因此，靶向基质ICAM-1可能构成一种对抗肿瘤细胞侵袭和扩散的可能治疗手段。
