title: CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction.
abstract: CD98hc (SLC3A2) is the heavy chain component of the dimeric transmembrane glycoprotein CD98, which comprises the large neutral amino acid transporter LAT1 (SLC7A5) in cells. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor prognosis clinically, but its exact contributions to tumorigenesis are uncertain. In this study, we showed that genetic deficiency of CD98hc protects against Ras-driven skin carcinogenesis. Deleting CD98hc after tumor induction was also sufficient to cause regression of existing tumors. Investigations into the basis for these effects defined two new functions of CD98hc that contribute to epithelial cancer beyond an intrinsic effect of CD98hc on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Second, CD98hc amplified the capacity of cells to respond to matrix rigidity, an essential factor in tumor development. Mechanistically, CD98hc mediated this stiffness sensing by increasing Rho kinase (ROCK) activity, resulting in increased transcription mediated by YAP/TAZ, a nuclear relay for mechanical signals. Our results suggest that CD98hc contributes to carcinogenesis by amplifying a positive feedback loop, which increases both extracellular matrix stiffness and resulting cellular responses. This work supports a rationale to explore the use of CD98hc inhibitors as cancer therapeutics.
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Soline
authors.initials: S
authors.lastname: Estrach
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: Sin-Ae
authors.initials: SA
authors.lastname: Lee
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Boulter
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. AFM Core facility, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pisano
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Errante
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Floriane S
authors.initials: FS
authors.lastname: Tissot
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cailleteau
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pons
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.affiliation: INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France. Avenir Team, University of Nice Sophia Antipolis, Nice, France. chloe.feral@inserm.fr.
authors.forename: Chloé C
authors.initials: CC
authors.lastname: Féral
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology; D000091102:YAP-Signaling Proteins; D018631:ras Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D027282:Fusion Regulatory Protein 1, Heavy Chain; D016023:Integrins; D010750:Phosphoproteins; C523212:Slc3A2 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; D054460:rho-Associated Kinases; D018631:ras Proteins