The four laboratories participating in this program will produce and use several models of human cancer to pursue at least three problems that inspire current work with mouse models -- maintenance (defining the functions required to maintain a viable tumor phenotype), fate determination (exploring the relationship between cellular components of a developmental lineage and the phenotypes of cells transformed by mutant cancer genes), and regeneration (testing for the existence and characteristics of cells responsible for sustained growth and recurrence of tumors, """"""""cancer stem cells"""""""").
Specific aims i nclude: (i) To identify genetic lesions required for maintenance of the essential features of malignancy, through the design and analysis of multi-step models of human cancer, affecting lung, ovarian, and pancreatic epithelium, fibroblasts, and hematopoietic cells (B cell and myeloid cell lineages); (ii) To characterize the interaction between cells in a developmental lineage and the oncogenic events that produce tumors of different phenotypes in that lineage, with emphasis on pancreatic, breast, and hematopoietic tumors; (iii) To identify cells within such tumors that are responsible for driving tumor growth and thus replenishing tumors after therapy; and (iv) To continue to refine several existing models (e.g. for lung, pancreatic, and breast carcinomas) and initiate new models (for fibrosarcoma, multiple myeloma, and promyelocytic leukemia) that facilitate the pursuit of aims (i), (ii), and (iii). We will employ traditional means for genetic alteration of the mouse germ line (transgenes and targeted mutations), as well as other methods for gene regulation, tissue- and cell type-specific effects and somatic cell gene delivery (e.g. with avian virus vectors, tetracycline-responsive regulators and inhibitory RNAs).
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|Mets, E; Van der Meulen, J; Van Peer, G et al. (2015) MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia. Leukemia 29:798-806|
|Pietras, Alexander; Katz, Amanda M; Ekström, Elin J et al. (2014) Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14:357-69|
|Mets, Evelien; Van Peer, Gert; Van der Meulen, Joni et al. (2014) MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia. Haematologica 99:1326-33|
|Squatrito, Massimo; Vanoli, Fabio; Schultz, Nikolaus et al. (2012) 53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma. Cancer Res 72:5250-60|
|Helmy, Karim; Halliday, John; Fomchenko, Elena et al. (2012) Identification of global alteration of translational regulation in glioma in vivo. PLoS One 7:e46965|
|Squatrito, Massimo; Brennan, Cameron W; Helmy, Karim et al. (2010) Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell 18:619-29|
|Reddy, Jay P; Peddibhotla, Sirisha; Bu, Wen et al. (2010) Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proc Natl Acad Sci U S A 107:3728-33|
|Du, Yi-Chieh Nancy; Klimstra, David S; Varmus, Harold (2009) Activation of PyMT in beta cells induces irreversible hyperplasia, but oncogene-dependent acinar cell carcinomas when activated in pancreatic progenitors. PLoS One 4:e6932|
|Charles, Nikki; Holland, Eric C (2009) Brain tumor treatment increases the number of cancer stem-like cells. Expert Rev Neurother 9:1447-9|
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