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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK052913-15A1
Application #
8812156
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
1998-09-25
Project End
2019-05-31
Budget Start
2014-09-25
Budget End
2015-05-31
Support Year
15
Fiscal Year
2014
Total Cost
$357,750
Indirect Cost
$132,750
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Goicoechea, S M; Garcia-Mata, R; Staub, J et al. (2014) Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts. Oncogene 33:1265-73
Cano, Carla E; Hamidi, Tewfik; Garcia, Maria Noe et al. (2014) Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis. Gut 63:984-95
Baumgart, Sandra; Chen, Nai-Ming; Siveke, Jens T et al. (2014) Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov 4:688-701
McCleary-Wheeler, Angela L; Lomberk, Gwen A; Weiss, Frank U et al. (2013) Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett 328:212-21
Hamidi, Tewfik; Cano, Carla E; Grasso, Daniel et al. (2013) NUPR1 works against the metabolic stress-induced autophagy-associated cell death in pancreatic cancer cells. Autophagy 9:95-7
Iovanna, Juan L; Marks, David L; Fernandez-Zapico, Martin E et al. (2013) Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer. Am J Pathol 182:1078-86
Lomberk, Gwen; Grzenda, Adrienne; Mathison, Angela et al. (2013) Kruppel-like factor 11 regulates the expression of metabolic genes via an evolutionarily conserved protein interaction domain functionally disrupted in maturity onset diabetes of the young. J Biol Chem 288:17745-58
Gilabert, Marine; Vaccaro, Maria Ines; Fernandez-Zapico, Martin E et al. (2013) Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs. J Cell Physiol 228:1834-43
Seo, Seungmae; Grzenda, Adrienne; Lomberk, Gwen et al. (2013) Epigenetics: a promising paradigm for better understanding and managing pain. J Pain 14:549-57
Paulo, Joao A; Urrutia, Raul; Kadiyala, Vivek et al. (2013) Cross-species analysis of nicotine-induced proteomic alterations in pancreatic cells. Proteomics 13:1499-512

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