This proposal requests the renewal of our major source of long-standing funding for investigating the epigenetics of pancreatic diseases. Our studies will directly extend our knowledge on common diseases, such as chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC), both painful and incurable disorders of the exocrine pancreas for which effective treatments remain to be discovered. Our OVERALL OBJECTIVE is to unravel novel epigenetic mechanisms that extend oncogenic growth signals downstream from KRAS during initiation and pancreatitis-associated cancer promotion. Our preliminary data identify HP1? as a pro-oncogenic epigenetic regulator of gene activation and growth, which is overexpressed in human pancreatic cancer as well as in animal models of pancreatic carcinogenesis. We provide solid evidence that this increased level of HP1? enhances the malignant effects of the KRAS oncogene. Our CENTRAL HYPOTHESIS is that the epigenetic regulator, HP1, works downstream from KRAS to promote pancreatic cell growth by regulating the expression of proliferative gene networks induced by this oncogene.
Our AIMS will test the following hypotheses:
Aim 1 : HP1? participates in a membrane-to-nucleus gene regulatory pathway that enhances the ability of KRAS to mediate neoplastic transformation and tumorigenesis;
Aim 2 : HP1? works downstream of KRAS to regulate growth-promoting gene networks;
and Aim 3 : HP1? inhibition ameliorates KrasG12D-mediated PDAC initiation and promotion after pancreatitis. Our design proposes molecular, cellular, and whole organism experiments using state-of-the-art methodologies. Accordingly our laboratory has developed the appropriate conceptual framework, reagents, trained personnel and has established productive collaborations. The innovative design of this proposal seeks to maximize the yield of mechanistic and rapidly translatable knowledge in this underepresented yet extremely the new promising area of epigenetics in pancreatic diseases. As new drugs targeting both the KRAS and HP1 pathways are being tested in clinical trials, this proposal builds the rationale for applying these tools to the management of patients affected with deadly pancreatic diseases, thereby bearing significant biomedical relevance.
This proposal examines new mechanisms by which genetic mutation (KRAS) and epigenetic, or above genetic, events cooperate to regulate cell growth in pancreatic ductal adenocarcinoma, a painful and deadly disease that ranks 4th in USA cancer deaths, for which no effective treatment currently exists. We will ascertain if disruption of these signals results in tumor regression. The results of these studies are germane to cancer biology and may build the rationale for the development and evaluation of new therapeutic strategies for the treatment of this dismal disease.
|Wang, Jianbo; Galvao, Joana; Beach, Krista M et al. (2016) Novel Roles and Mechanism for KrÃ¼ppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells. J Biol Chem 291:18084-95|
|Loncle, C; Molejon, M I; Lac, S et al. (2016) The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation. Cell Death Dis 7:e2295|
|Branham, M T; Campoy, E; Laurito, S et al. (2016) Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer. Breast Cancer Res Treat 155:13-23|
|Lomberk, Gwen A; Iovanna, Juan; Urrutia, Raul (2016) The promise of epigenomic therapeutics in pancreatic cancer. Epigenomics 8:831-42|
|Velez, Gabriel; Lin, Marisa; Christensen, Trace et al. (2016) Evidence supporting a critical contribution of intrinsically disordered regions to the biochemical behavior of full-length human HP1Î³. J Mol Model 22:12|
|Papadakis, Konstantinos A; Krempski, James; Svingen, Phyllis et al. (2015) KrÃ¼ppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation. Am J Physiol Gastrointest Liver Physiol 309:G900-9|
|Grasso, Daniel; Bintz, Jennifer; Lomberk, Gwen et al. (2015) Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation. Sci Rep 5:17549|
|Urrutia, Raul A; Kalinec, Federico (2015) Biology and pathobiology of lipid droplets and their potential role in the protection of the organ of Corti. Hear Res 330:26-38|
|MitiÄ‡, Tijana; Caporali, Andrea; Floris, Ilaria et al. (2015) EZH2 modulates angiogenesis in vitro and in a mouse model of limb ischemia. Mol Ther 23:32-42|
|De Assuncao, Thiago M; Sun, Yan; Jalan-Sakrikar, Nidhi et al. (2015) Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. Lab Invest 95:684-96|
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