Basic Research Team 5 "Epithelial homeostasis and tumorigenesis"
Dr Chloé FERAL, CR1 INSERM, Team Leader
Figure 1. CD98 heterodimer : the heavy subunit (pink) and the light subunit (blue) are linked by a disulfide bridge (yellow) with conserved cysteine residues(from Palacin M. et al. Physiology, Vol. 20, No. 2, 112-124, April 2005)
The cells that compose the epithelium are constantly renewed. To maintain homeostasis in an adult tissue, cell proliferation must be tightly regulated, yet how this is controlled is not fully understood. When this balance is lost and too many cells accumulate, epithelial cancers (or carcinomas) arise. In particular, squamous cell carcinoma (SCC) is the second most common type of skin cancer and its incidence increases with age. Our lab is investigating the role of CD98hc, a dual function transmembrane protein, in epidermal tumor formation.
Epithelial cells rest on a basal membrane composed of highly organized network of extracellular matrix (ECM) proteins. Tumor formation greatly depend on cell adhesion, migration and proliferation which are regulated by both ECM and integrins, a family of cell-surface receptors that interact with ECM proteins. Integrins function as bi-directional signaling molecules.
CD98, originally identified as the 4F2 antigen, is highly expressed in keratinocytes. Its expression also correlates with increased morphological grade and worsened prognosis of tumors, independent of their tissue of origin. CD98 is a heterodimer of a common heavy chain (CD98hc, SLC3A2), and one of several light chains (CD98lc) that each has multiple membrane spanning domains. CD98hc has two main functions: amino acid transporter (via its interaction with a CD98lc) and integrin signaling modulator (via its interaction with β integrins). Its knock-out is embryonic lethal.
The CD98hc-integrin complex plays a crucial role in cell behavior that depends on cell proliferation, migration and survival. Besides, the CD98 heterodimer (heavy chain and light chain) contributes to efficient amino-acid transport, which is vital for cell survival and proliferation.
Our work aims at determining how CD98 interactions contribute to epidermal homeostasis and tumorigenesis.
Figure 2. CD98hc Expression in the basal layer of human epidermis (green CD98hc, blue DAPI)
Previously generated CD98hcfl/fl murine line will be used to determine the role of CD98hc in epidermal homeostasis and skin cancer in vivo. Furthermore, we will decipher the cellular and molecular events resulting from CD98hc deletion in vitro.
The proposed work will revolve around 3 main axes :
1) Determine the role of CD98hc in skin homeostasis and tumorigenesis in vivo
2) Analyze in vitro CD98hc implication in regulating integrin function and amino-acid transport in murine keratinocytes
3) Investigate the molecular mechanisms involved downstream of CD98hc and assess the roles of the different CD98hc domains on its biological activities.
CD98hc (SLC3A2) Regulation of Skin Homeostasis Wanes with Age. Boulter E, Estrach S, Errante A, Pons C, Cailleteau L, Tissot F, Meneguzzi G, Féral CC. J Exp Med. 2013 Jan 14;210(1):173-90. doi: 10.1084/jem.20121651. Epub 2013 Jan 7.PMID: 23296466.
Adipocytes Secrete Leukotrienes : Contribution to Obesity-Associated Inflammation and Insulin Resistance in Mice. Mothe-Satney I, Filloux C, Amghar H, Pons C, Bourlier V, Galitzky J, Grimaldi PA, Féral CC, Bouloumié A, Van Obberghen E, Neels JG. Diabetes. 2012 Sep.61(9):2311-9.
Increases Renal Epithelial Cell Proliferation by Activating MAPKs. Bulus N, Feral C, Pozzi A, Zent R., PLoS One. 2012 ;7(6):e40026. Epub 2012 Jun 29.
Off the beaten paths : alternative and crosstalk regulation of Rho GTPases. Boulter E, Estrach S, Garcia-Mata R, Féral CC. FASEB J. 2011 Oct 28. PMID : 22038046
ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Sanz-Moreno V, Gaggioli C, Yeo M, Albrengues J, Wallberg F, Viros A, Hooper S, Mitter R, Féral CC, Cook M, Larkin J, Marais R, Meneguzzi G, Sahai E, Marshall CJ. Cancer Cell. 2011 Aug 16;20(2):229-45. PMID:21840487
Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Garmy-Susini B, Avraamides CJ, Schmid MC, Foubert P, Ellies LG, Barnes L, Feral C, Papayannopoulou T, Lowy A, Blair SL, Cheresh D, Ginsberg M, Varner JA. Cancer Res. 2010 Apr 15;70(8):3042-51. 2010 Apr 13. PMID:20388801
Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2). Fogelstrand P, Féral CC, Zargham R, Ginsberg MH. J Exp Med. 2009 Oct 26;206(11):2397-406. 2009 Oct 19. PMID:19841087
CD98hc facilitates B cell proliferation and adaptive humoral immunity. Cantor J, Browne CD, Ruppert R, Féral CC, Fässler R, Rickert RC, Ginsberg MH. Nat Immunol. 2009 Apr;10(4):412-9. Epub 2009 Mar 8. PMID:19270713
Differences in regulation of Drosophila and vertebrate integrin affinity by talin. Helsten TL, Bunch TA, Kato H, Yamanouchi J, Choi SH, Jannuzi AL, Féral CC, Ginsberg MH, Brower DL, Shattil SJ. Mol Biol Cell. 2008 Aug;19(8):3589-98. Epub 2008 May 28. PMID:18508915
Blockade of alpha4 integrin signaling ameliorates the metabolic consequences of high-fat diet-induced obesity. Féral CC, Neels JG, Kummer C, Slepak M, Olefsky JM, Ginsberg MH. Diabetes. 2008 Jul;57(7):1842-51. Epub 2008 Apr 21. PMID:18426864
CD98hc (SLC3A2) interaction with the integrin beta subunit cytoplasmic domain mediates adhesive signaling. Prager GW, Féral CC, Kim C, Han J, Ginsberg MH. J Biol Chem. 2007 Aug 17;282(33):24477-84. Epub 2007 Jun 27. PMID:17597067
CD98hc (SLC3A2) participates in fibronectin matrix assembly by mediating integrin signaling. Féral CC, Zijlstra A, Tkachenko E, Prager G, Gardel ML, Slepak M, Ginsberg MH. J Cell Biol. 2007 Aug 13;178(4):701-11. Epub 2007 Aug 6. PMID:17682053
Blocking the alpha 4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. Féral CC, Rose DM, Han J, Fox N, Silverman GJ, Kaushansky K, Ginsberg MH. J Clin Invest. 2006 Mar;116(3):715-23. Epub 2006 Feb 9. PMID:16470243
CD98hc (SLC3A2) mediates integrin signaling. Feral CC, Nishiya N, Fenczik CA, Stuhlmann H, Slepak M, Ginsberg MH. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):355-60. Epub 2004 Dec 29. PMID:15625115