A postdoctoral project is proposed by Stephanie C. Casey at the Department of Medicine, Division of Oncology at Stanford University under the sponsor Dr. Dean Felsher. This project will help understand how the immune system contributes to tumors caused by oncogenes. The Felsher laboratory studies how oncogenes initiate and maintain tumorigenesis. Oncogenes are genes that, when mutated, have the potential to turn a normal cell into a cancerous cell. Our laboratory utilizes the Tet-system to generate transgenic mouse models to modulate expression of select genes, such as the oncogene MYC (one of the most commonly dysregulated genes in human cancer), as well as other oncogenes such as RAS, BCR-ABL, and BCL2, both independently and cooperatively. We have found oncogene inactivation elicits dramatic tumor regression, and we have shown that a functioning immune system is essential to elicit oncogene addiction. During the proposed training, this project will elucidate how CD4+ T cells, an immune cell previously demonstrated by the Felsher laboratory to be crucial for sustained tumor regression, contribute to the tumor microenvironment. The project will test whether these CD4+ T cells express anti-angiogenic Thrombospondin-1 (TSP-1), assist in the development of senescence, and recruit B cells to generate anti-tumor memory. The Felsher lab's specialized transgenic mouse tools allow for an exceptional approach to examine oncogene signaling in the context of tumor microenvironment. The anticipated outcome of this project is an increased understanding of how parts of the adaptive immune system may be targeted alongside oncogenes to treat cancer. Future experiments may validate our results in human patients. The impact of this work may have implications for novel """"""""druggable"""""""" therapeutic targets and will assist in the development of new cancer treatments. This research will help broaden the current understanding of how the immune system contributes to tumor growth and tumor regression. Furthermore, the findings from this study may provide insight as to the potential use of TSP-1 as an anti-cancer therapy. The applicant is highly motivated and aims to pursue an academic research career as an independent investigator in the field of cancer biology. The applicant has designed specific experiments to test targeted hypotheses using novel transgenic mouse models. Techniques such as mouse models, culture of primary cells and cell lines, flow cytometry and cell sorting, gene and protein expression studies, multi-parameter imaging modalities, and in vitro studies will be used. !

Public Health Relevance

This project will study the role of the immune system in mediating the effects of cancer therapy. Using novel transgenic mouse models of leukemia/lymphoma caused by excess amounts of the MYC oncogene, this research proposal will investigate the contribution of specific immune cells (called CD4+ T cells) and a protein they make (called Thrombospondin-1) in curative tumor clearance when MYC is inhibited. The findings herein will provide crucial information into the mechanisms that govern cancer therapy and may lead to future advances in our ability to treat human leukemia/lymphoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F09-L (20))
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Jakowlew, Sonia B
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Casey, Stephanie C; Tong, Ling; Li, Yulin et al. (2016) MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352:227-31
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304
Casey, Stephanie C; Vaccari, Monica; Al-Mulla, Fahd et al. (2015) The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 36 Suppl 1:S160-83
Casey, Stephanie C; Amedei, Amedeo; Aquilano, Katia et al. (2015) Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol 35 Suppl:S199-S223
Casey, Stephanie C; Li, Yulin; Felsher, Dean W (2014) An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. Immunol Res 58:282-91
Cao, Zhongwei; Ding, Bi-Sen; Guo, Peipei et al. (2014) Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell 25:350-65
Li, Y; Casey, S C; Felsher, D W (2014) Inactivation of MYC reverses tumorigenesis. J Intern Med 276:52-60
Li, Yulin; Choi, Peter S; Casey, Stephanie C et al. (2014) MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell 26:262-72
Casey, Stephanie C; Bellovin, David I; Felsher, Dean W (2013) Noncanonical roles of the immune system in eliciting oncogene addiction. Curr Opin Immunol 25:246-58