While it is known that carcinogenesis stems from unregulated epithelial proliferation and invasion, additional information is needed about the mechanistic events controlling these two critical processes. Uncontrolled Shh target gene induction promotes growth and invasion of up to 25% of human cancers. While previous studies indicate that the Ci/Gli family of zinc finger transcription factors mediates the transcriptional effects of Shh, the mechanisms for Shh-dependent growth and migration/invasion during tumorigenesis remain poorly understood. We have identified a novel Shh pathway member, Missing in Metastasis (MIM), whose levels are altered in a variety of epithelial cancers. MIM cooperates with the Gli oncogene to recapitulate Shh-mediated epithelial proliferation and invasion. MIM has two separable functions: regulation of Shh target gene induction, and control of stimuli-induced cellular migration. MIM stimulates maximal Shh target gene induction by binding to and antagonizing Sufu, the central negative regulator of the pathway. MIM regulates cellular migration by assembling protein complexes that control cortical actin filament assembly. Normal migration of Drosophila primordial germ cells (PGCs) requires precise cytoskeletal response to local tissue migratory cues that include mesoderm-derived hedgehog. We have shown that Drosophila MIM (dMIM) mutant PGCs fail to respond to these local cues and metastasize to ectopic locations. The goal of this proposal is to dissect these documented MIM functions using human and Drosophila tissue models.
We aim to 1) elucidate the mechanism of MIM potentiation of Gli transcription by assaying MIM activity in different states of the Shh pathway, determine which Sufu activity MIM antagonizes and identify the Sufu protein surface with which MIM interacts;2) establish the role of MIM in a human model of Shh-dependent tumorigenesis by determining which MIM function contributes to Shh-dependent human carcinogenesis, and how MIM contributes to Shh-dependent tumor induction and maintenance;3) analyze dMIM function in PGC migration by categorizing cytoskeletal changes in dMIM mutant PGCs, identify the genetic and biochemical interactions of dMIM with other cytoskeletal regulators, and identify dMIM functional domains through the generation of additional dMIM missense alleles. The funding of this proposal will lead to a greater understanding of the mechanisms of epithelial growth and invasion by Shh signaling and may lead to new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052785-04
Application #
7849553
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Baker, Carl
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$326,832
Indirect Cost
Name
Stanford University
Department
Dermatology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Atwood, Scott X; Oro, Anthony E (2014) ""Atypical"" regulation of Hedgehog-dependent cancers. Cancer Cell 25:133-4
Melo, Sandra P; Lisowski, Leszek; Bashkirova, Elizaveta et al. (2014) Somatic correction of junctional epidermolysis bullosa by a highly recombinogenic AAV variant. Mol Ther 22:725-33
Atwood, Scott X; Whitson, Ramon J; Oro, Anthony E (2014) Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med 4:a013581
Atwood, Scott X; Whitson, Ramon J; Oro, Anthony E (2013) ""Patch""ing up our tumor signaling knowledge. J Invest Dermatol 133:1131-3
Woo, Wei-Meng; Atwood, Scott X; Zhen, Hanson H et al. (2013) Rapid genetic analysis of epithelial-mesenchymal signaling during hair regeneration. J Vis Exp :e4344
Aasi, Sumaira; Silkiss, Rona; Tang, Jean Y et al. (2013) New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol 149:242-3
Yucel, Gozde; Altindag, Banu; Gomez-Ospina, Natalia et al. (2013) State-dependent signaling by Cav1.2 regulates hair follicle stem cell function. Genes Dev 27:1217-22
Atwood, Scott X; Li, Mischa; Lee, Alex et al. (2013) GLI activation by atypical protein kinase C ?/? regulates the growth of basal cell carcinomas. Nature 494:484-8
Chang, Anne Lynn S; Oro, Anthony E (2012) Initial assessment of tumor regrowth after vismodegib in advanced Basal cell carcinoma. Arch Dermatol 148:1324-5
Gomez-Ospina, Natalia; Chang, Anne Lynn S; Qu, Kun et al. (2012) Translocation affecting sonic hedgehog genes in basal-cell carcinoma. N Engl J Med 366:2233-4

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