Sonic hedgehog (Shh) signaling plays a crucial role in human development with inappropriate pathway activity associated with a variety of human birth defects and up to 25% of human cancers including cutaneous basal cell carcinomas (BCCs). Our unifying hypothesis supported by data gathered in the previous round of funding is that cell-intrinsic Shh target gene induction in BCC epithelium is regulated by specific signals from the surrounding stromal cells. We have focused on identifying both the tumor cell-intrinsic (TFs) and the non-cell autonomous stromal factors (SFs) that affect Shh target gene induction and tumor function. Our results point to three cell-intrinsic mechanisms that regulate Shh target gene induction in the epithelium: 1) regulation of Gli transcription, 2) regulation of Gli protein destruction, and 3) regulation of Gli activity through accessory transcription factors such as Missing in Metastasis. We have demonstrated that tumor formation depends on epithelial Gli protein accumulation. Gli is destroyed in a proteasome-dependent manner through two distinct, conserved destruction signals Dn and DC. Removal of these degrons stabilizes Gli1 and rapidly accelerates BCC formation in mice. Separate studies using a novel assay for stromal activity have identified SF1 as the BMP antagonist gremlin that is capable of maintaining epithelial Shh responsiveness in the absence of stroma. Gremlin is expressed in a small subset of cells normally and in cells surrounding BCCs, and induces GN2 transcription, thus establishing a mechanistic link between tumor and stromal activity. The focus of the current renewal is to understand, using human and mouse tissue models we have developed, how cell-intrinsic step 2 and the newly identified SF1, gremlin, maintain Shh target gene induction and tumor growth. We will: 1) Elucidate the mechanism of Gli protein destruction by defining the contribution of each degron to BCC development, establish the impact of stabilized Gli on tumor development, and identify the signaling pathways that regulate Gli destruction; 2) Define the mechanism of gremlin-dependent stromal activity by elucidating the mechanism of gremlin-mediated potentiation of Shh signaling, and establishing a tissue role for gremlin in human and mouse BCC development. This effort is based on the premise that understanding Shh- dependent tumor-stroma interactions in the skin will lead to new insights into tumorigenesis, with a goal toward new therapeutics for human birth defects and epithelial tumors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046786-07
Application #
7288332
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Baker, Carl
Project Start
2000-04-01
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
7
Fiscal Year
2007
Total Cost
$333,362
Indirect Cost
Name
Stanford University
Department
Dermatology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Kuonen, François; Surbeck, Isabelle; Sarin, Kavita Y et al. (2018) TGF?, Fibronectin and Integrin ?5?1 Promote Invasion in Basal Cell Carcinoma. J Invest Dermatol 138:2432-2442
Whitson, Ramon J; Lee, Alex; Urman, Nicole M et al. (2018) Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nat Med 24:271-281
Whitson, Ramon J; Oro, Anthony E (2017) Soil Primes the Seed: Epigenetic Landscape Drives Tumor Behavior. Cell Stem Cell 20:149-150
Mirza, Amar N; Fry, Micah A; Urman, Nicole M et al. (2017) Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment. JCI Insight 2:
Wang, Kevin; Lee, Carolyn S; Marinkovich, M Peter et al. (2016) Factors That May Promote an Effective Local Research Environment. J Invest Dermatol 136:1529-1531
Kwon, Gina P; Ally, Mina Sarah; Bailey-Healy, Irene et al. (2016) Update to an open-label clinical trial of vismodegib as neoadjuvant before surgery for high-risk basal cell carcinoma (BCC). J Am Acad Dermatol 75:213-5
Danial, Christina; Sarin, Kavita Y; Oro, Anthony E et al. (2016) An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib. Clin Cancer Res 22:1325-9
Urman, Nicole M; Mirza, Amar; Atwood, Scott X et al. (2016) Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions. PLoS One 11:e0168031
Ally, Mina S; Ransohoff, Katherine; Sarin, Kavita et al. (2016) Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. JAMA Dermatol 152:452-6
Atwood, Scott X; Sarin, Kavita Y; Li, Jiang R et al. (2015) Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma. J Invest Dermatol 135:2138-2141

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