We are requesting support to continue our membership in the MMHCC. During the current grant period, we have generated and analyzed several mouse models for human FAP and HNPCC. We have also modeled loss of heterozygosity in mice and a point mutation of MSH6 that provided new insights into GI tumorigenesis. The active investigators of our program are Kucherlapati, Edelmann and Lipkin. In this application Dr. Rakesh Jain of MGH, an expert in intravital imaging will join our group. Patients with germline mutations in APC develop FAP and Gardner syndrome and those with germline mutations in MLH1 and MSH2 develop HNPCC. Both of these disorders are characterized by tumors in the GI tract and other locations in the body. These results suggest that mutations in these genes are initiating events in a number of different tumor types. We propose to use the cre-loxP system to make conditional knockout mice to generate mouse models for tumors in the skin, breast and other tissues. These mice will also be used to model sporadic colorectal tumorigenesis by inactivating the gene in somatic colorectal mucosa. This will be accomplished by introducing Adeno-cre by enema. Adeno-cre will also be used to generate sporadic mouse models for skin and lung cancer. To follow the cells that have undergone the targeted gene inactivation, we propose to develop a novel system, in which gene inactivation results in the simultaneous activation of a cellular marker such as beta-galactosidase or green fluorescent protein (GFP). The natural history of the tumors will be examined by conventional methods as well as by intravital microscopy. We propose to construct a multiphoton laser scanning micro-endoscope that can be used image colorectal tumor progression in mice with a very high resolution. Intravital imaging will also be used to examine angiogenesis in our tumor models. We propose a novel approach to examine gene-environment interactions. For example to study the role of obesity we will combine Apc or Msh2 mutant mice with ob/ob mice that normally become obese. We also propose to examine the very early and very late stages of tumor formation by using the cellular tagging approach mentioned above. All of these studies will be augmented by genomic approaches that facilitate discovery of new genes and pathways that are critical for the development of tumors in the Apc, Mlhl and Msh2 mutant mice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1-SRRB-U (J1))
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Marks, Cheryl L
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Brigham and Women's Hospital
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Esfahani, Shadi A; Heidari, Pedram; Kim, Sun A et al. (2016) Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors. Theranostics 6:2028-2038
Arvold, Nils D; Heidari, Pedram; Kunawudhi, Anchisa et al. (2016) Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET. Technol Cancer Res Treat 15:234-42
Sheth, Rahul A; Arellano, Ronald S; Uppot, Raul N et al. (2015) Prospective trial with optical molecular imaging for percutaneous interventions in focal hepatic lesions. Radiology 274:917-26
Heidari, Pedram; Esfahani, Shadi A; Turker, Nazife S et al. (2015) Imaging of Secreted Extracellular Periostin, an Important Marker of Invasion in the Tumor Microenvironment in Esophageal Cancer. J Nucl Med 56:1246-51
Heidari, Pedram; Deng, Francis; Esfahani, Shadi A et al. (2015) Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader. Clin Cancer Res 21:1340-7
Kuruppu, Darshini; Brownell, Anna-Liisa; Shah, Khalid et al. (2014) Molecular imaging with bioluminescence and PET reveals viral oncolysis kinetics and tumor viability. Cancer Res 74:4111-21
Habibollahi, Peiman; Waldron, Todd; Heidari, Pedram et al. (2014) Fluorescent nanoparticle imaging allows noninvasive evaluation of immune cell modulation in esophageal dysplasia. Mol Imaging 13:1-11
Li, Xingnan; Nadauld, Lincoln; Ootani, Akifumi et al. (2014) Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat Med 20:769-77
Turker, N Selcan; Heidari, Pedram; Kucherlapati, Raju et al. (2014) An EGFR targeted PET imaging probe for the detection of colonic adenocarcinomas in the setting of colitis. Theranostics 4:893-903
Kucherlapati, Melanie H; Esfahani, Shadi; Habibollahi, Peiman et al. (2013) Genotype directed therapy in murine mismatch repair deficient tumors. PLoS One 8:e68817

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