Members of the cadherin family of cell-cell adhesion molecules are well-established players in tumor progression, but the importance of the desmosomal cadherin sub-class is poorly understood. Of particular interest is the desmoglein (Dsg) subfamily, three of which are distributed in distinct patterns within the self-renewing, complex epithelia of the oral cavity. Our overarching hypothesis is that Dsgs regulate homeostasis by sustaining proliferation in the basal layer while promoting differentiation as cells stratify, and that alterations occurring during tumor progression upset this balance. This proposal focuses on desmoglein 1 (Dsg1), which, among cadherins tested, was uniquely associated with poor patient outcome in head and neck squamous cell carcinoma (HNSCC). Dsg1 is expressed as cells emerge from the basal layer to differentiate and form a protective barrier. We showed that Dsg1 actively participates in epithelial morphogenesis by promoting a differentiation program in epidermal keratinocytes, via suppression of ErbB/MAPK signaling. Importantly, over 90% of HNSCC express elevated ErbB1. We hypothesize that Dsg1 regulates homeostasis in HNSCC by promoting differentiation while limiting tumor progression through an interaction with the ErbB binding protein ERBIN, and that bi-directional interactions between Dsgs and membrane bound sheddases in the ADAM family further regulate tumor cell fate.
Our aims are to: 1) test the hypothesis that Dsg1 promotes a program of HNSCC differentiation, to test whether this occurs by attenuating MAPK signaling, and to determine whether Dsg1 loss is associated with suppressed differentiation and increased proliferation/invasion in an animal model and human HNSCCs, 2) determine whether the scaffolding protein, ERBIN, mediates Dsg1-dependent signaling in vitro and in vivo by interfering with a Ras/Raf/Shoc2 complex, and 3) test the hypothesis that Dsgs are both substrates and inhibitors of ADAM sheddase activity and determine the impact of this bi-directional relationship on Dsg-dependent adhesion and signaling in vitro, and tumor progression in vivo. Knowledge gained from this study holds promise for the design of innovative therapies including those that circumvent resistance to drugs targeting upstream players in the ErbB/MAPK pathway.

Public Health Relevance

This project aims to understand how sticky molecules called desmogleins on the surface of head and neck squamous cell carcinoma (HNSCC) cells perform functions beyond their role in cell coherence, to regulate tumor cell behavior and tumor progression. Knowledge gained from these studies holds promise for addressing the diagnostic and therapeutic challenges associated with HNSCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122151-07
Application #
8543650
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ault, Grace S
Project Start
2006-07-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$244,189
Indirect Cost
$82,176
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Nekrasova, Oxana; Harmon, Robert M; Broussard, Joshua A et al. (2018) Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination. Nat Commun 9:1053
Rübsam, Matthias; Broussard, Joshua A; Wickström, Sara A et al. (2018) Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective. Cold Spring Harb Perspect Biol 10:
Yang, Ruiguo; Broussard, Joshua A; Green, Kathleen J et al. (2018) Techniques to stimulate and interrogate cell-cell adhesion mechanics. Extreme Mech Lett 20:125-139
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Broussard, Joshua A; Yang, Ruiguo; Huang, Changjin et al. (2017) The desmoplakin-intermediate filament linkage regulates cell mechanics. Mol Biol Cell 28:3156-3164
Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430
Jones, Jonathan C R; Kam, Chen Yuan; Harmon, Robert M et al. (2017) Intermediate Filaments and the Plasma Membrane. Cold Spring Harb Perspect Biol 9:
Broussard, Joshua A; Green, Kathleen J (2017) Research Techniques Made Simple: Methodology and Applications of Förster Resonance Energy Transfer (FRET) Microscopy. J Invest Dermatol 137:e185-e191
Najor, Nicole Ann; Fitz, Gillian Nicole; Koetsier, Jennifer Leigh et al. (2017) Epidermal Growth Factor Receptor neddylation is regulated by a desmosomal-COP9 (Constitutive Photomorphogenesis 9) signalosome complex. Elife 6:
Arnette, Christopher; Koetsier, Jennifer L; Hoover, Paul et al. (2016) In Vitro Model of the Epidermis: Connecting Protein Function to 3D Structure. Methods Enzymol 569:287-308

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