Hedgehog (Hh) signaling plays instructive roles in normal embryonic patterning, but pathological pathway activity in post-embryonic tissues is associated with the growth of tumor types that together account for approximately 25% of cancer deaths. Normal post-embryonic roles for activation of the Hh signaling pathway and its sister, the Wnt pathway, have been demonstrated in renewal and maintenance of tissue stem cells. These findings are of potential relevance to cancer because of the possible derivation of cancer stem cells, the minority of cells within a cancer that are capable of its propagation, from adult tissue stem cells. Pathway activity and expansion of progenitor cell pools also are associated with the response to acute injury, and chronic tissue injury furthermore results in increased risk for cancers of the types associated with Hh and Wnt pathway activity. Cancer growth thus resembles the activated state of acute injury repair, and the incidence of cancerous growth increases with the occurrence of repeated injury. These observations suggest the central hypothesis and several corollaries to be tested in this proposal, namely, that cancer growth represents the continuous operation of an unregulated state of tissue repair, that continuous Hh pathway activity in carcinogenesis is a deviation from the return to quiescence that normally follows regeneration, and that tissue stem cells are the relevant cell types. This hypothesis will be tested in the context of Hh pathway-dependent cancers by identifying and isolating cancer stem cells, by comparing these cancer stem cells to each other and to endogenous tissue stem or progenitor cells, and by examining the role and mechanism of Hh pathway activation in tissue repair and in tumorigenesis.
The specific aims are: 1. To identify and isolate cancer stem cells within established cell lines or primary cell cultures derived from endodermal tumors that depend upon Hedgehog pathway activity for growth. 2. To identify and isolate candidate stem cells from corresponding resting or injured endodermal organs. 3. To compare the characteristics of cancer stem cells and tissue stem cells from these endodermal organs. 4. To investigate the molecular basis of injury-induced responsiveness to Hh protein signals in normal tissues and the basis of continuous response in tumors. These studies will provide a fundamental basis for design and optimization of strategies to manipulate pathway activity in cancer therapy and in tissue regeneration. An understanding of the mechanistic basis for regulation of Hh responsiveness also has the potential to foster long-term strategies for cancer prevention.

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National Cancer Institute (NCI)
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Janes, K; Symons-Liguori, A M; Jacobson, K A et al. (2016) Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics. Br J Pharmacol 173:1253-67
Oh, Sekyung; Kato, Masaki; Zhang, Chi et al. (2015) A Comparison of Ci/Gli Activity as Regulated by Sufu in Drosophila and Mammalian Hedgehog Response. PLoS One 10:e0135804
Price, Jessica C; Pollock, Lana M; Rudd, Meghan L et al. (2014) Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. PLoS One 8:e63313
O'Donnell, Kathryn A; An, Wenfeng; Schrum, Christina T et al. (2013) Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene-trap mouse model. Proc Natl Acad Sci U S A 110:E2706-13
Newman, Robert H; Hu, Jianfei; Rho, Hee-Sool et al. (2013) Construction of human activity-based phosphorylation networks. Mol Syst Biol 9:655
Gnanakkan, Veena P; Jaffe, Andrew E; Dai, Lixin et al. (2013) TE-array--a high throughput tool to study transposon transcription. BMC Genomics 14:869
Rybanska-Spaeder, Ivana; Reynolds, Taylor L; Chou, Jeremy et al. (2013) 53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation. Mol Cancer Res 11:1223-34
Le Gallo, Matthieu; O'Hara, Andrea J; Rudd, Meghan L et al. (2012) Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 44:1310-5
O'Donnell, Kathryn A; Keng, Vincent W; York, Brian et al. (2012) A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer. Proc Natl Acad Sci U S A 109:E1377-86
Burns, Kathleen H; Boeke, Jef D (2012) Human transposon tectonics. Cell 149:740-52

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