title: LIF mediates proinvasive activation of stromal fibroblasts in cancer.
abstract: Signaling crosstalk between tumor cells and fibroblasts confers proinvasive properties to the tumor microenvironment. Here, we identify leukemia inhibitory factor (LIF) as a tumor promoter that mediates proinvasive activation of stromal fibroblasts independent of alpha-smooth muscle actin (α-SMA) expression. We demonstrate that a pulse of transforming growth factor β (TGF-β) establishes stable proinvasive fibroblast activation by inducing LIF production in both fibroblasts and tumor cells. In fibroblasts, LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, which results in collective carcinoma cell invasion in vitro and in vivo. Accordingly, carcinomas from multiple origins and melanomas display strong LIF upregulation, which correlates with dense collagen fiber organization, cancer cell collective invasion, and poor clinical outcome. Blockade of JAK activity by Ruxolitinib (JAK inhibitor) counteracts fibroblast-dependent carcinoma cell invasion in vitro and in vivo. These findings establish LIF as a proinvasive fibroblast producer independent of α-SMA and may open novel therapeutic perspectives for patients with aggressive primary tumors.
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, F-06107 Nice, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Albrengues
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, F-06107 Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourget
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, F-06107 Nice, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pons
authors.affiliation: Pathological Anatomy and Cytology Laboratory, 270 Avenue Sainte-Marguerite, F-06200 Nice, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Butet
authors.affiliation: Laboratory of Clinical and Experimental Pathology and Hospital-Integrated Tumor Biobank, Pasteur Hospital, F-06002 Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: INSERM, U1065, Mediterranean Centre for Molecular Medicine (C3M), University of Nice Sophia Antipolis, F-06204 Nice, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tartare-Deckert
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, F-06107 Nice, France.
authors.forename: Chloe C
authors.initials: CC
authors.lastname: Feral
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, F-06107 Nice, France.
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, F-06107 Nice, France. Electronic address: gaggioli@unice.fr.
authors.forename: Cedric
authors.initials: C
authors.lastname: Gaggioli
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009570:Nitriles; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D000199:Actins; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; C540383:ruxolitinib; D000205:Actomyosin; D053612:Janus Kinases