The targeted inactivation of oncogene can elicit robust cell death suggesting that tumors can be """"""""addicted"""""""" to a mutated proto-oncogene. Understanding why and predicting when tumors are addicted to oncogenes would have protean implications for the development of therapies for cancer. This would enable a more rational basis for choosing molecular targets, identify potentially new non-oncogene targets, facilitate the screening for potential agents and provide a strategy for selecting patients most likely to benefit from specific targeted therapeutic. To study oncogene addiction, we have used the Tet system to develop conditional transgenic mouse models. We have created several conditional oncogenes (MYC, RAS, BCL-2, BCR-ABL), to create transgenic mouse models of different cancers including: T-acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), osteogenic sarcoma (OS), and hepatocellular carcinoma (HCC). We have found that the consequences of oncogene inactivation are dependent upon both cellular and genetic context. Oncogene addiction involves tumor cell intrinsic and host dependent programs including the permanent loss of self- renewal or induction of cellular senescence and host-dependent programs. We are in the position to now define more generally how these mechanisms contribute oncogene inactivation induced cel death. Our hypothesis is that oncogene addiction can be modeled as a differential response between cel death and survival signaling. We will define key lynch pin gene products and pathways. Our approach will be to perform a quantitative in situ analysis using intravital microscopy and imunohistochemistry combined with a comparative proteomic and genomic analysis. We will perform these studies using different conditional oncogenes and types of cancer in different genetic contexts and then use mathematical modeling and computational biological approaches to reveal the common lynch pin genes and define their mechanistic role in oncogene addiction.
Oncogene inactivation can elicit the phenomenon of oncogene addiction. Understanding the mechanism by which oncogene inactivation induces cell death would have broad implications for the development of therapies for cancer.
|Li, Yulin; Deutzmann, Anja; Choi, Peter S et al. (2016) BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia. Oncotarget 7:26926-34|
|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|
|Yetil, Alper; Anchang, Benedict; Gouw, Arvin M et al. (2015) p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia. Oncotarget 6:3563-77|
|Goodson 3rd, William H; Lowe, Leroy; Carpenter, David O et al. (2015) Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 36 Suppl 1:S254-96|
|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:S199-223|
|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:S276-304|
|Shroff, Emelyn H; Eberlin, Livia S; Dang, Vanessa M et al. (2015) MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci U S A 112:6539-44|
|Li, Y; Casey, S C; Felsher, D W (2014) Inactivation of MYC reverses tumorigenesis. J Intern Med 276:52-60|
|Ansari, Celina; Tikhomirov, Grigory A; Hong, Su Hyun et al. (2014) Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small 10:566-75, 417|
|Ye, Deju; Shuhendler, Adam J; Cui, Lina et al. (2014) Bioorthogonal cyclization-mediated in situ self-assembly of small-molecule probes for imaging caspase activity in vivo. Nat Chem 6:519-26|
Showing the most recent 10 out of 26 publications