Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with an overall 5-year survival rate of 6%. The molecular mechanisms that contribute to the biological aggressiveness of PDAC are being gradually elucidated, and the crucial role of high and low frequency driver mutations in PDAC is providing new insights into the complexity of this cancer. However, the widespread consequences of aberrant transforming growth factor-beta (TGF-beta) actions in PDAC in the context of the presence of oncogenic Kras and loss of function of the retinoblastoma protein are not well understood. In this proposal we will use a novel genetically engineered mouse model (GEM) of PDAC that we generated in which oncogenic Kras is combined with RB deletion. The resultant KRC mice rapidly develop pancreatic intraepithelial (PanIN) lesions that progress to PDAC within weeks after birth, and the pancreatic cancer cells in these cancers are highly proliferative. Based on our published data and preliminary results, the KRC mouse will allow us to test the hypothesis that aberrant TGF-beta signaling in PDAC synergizes with RB inactivation, leading to deleterious actions by TGF-beta, aberrant mitogenic signaling, and enhanced pancreatic cancer cell proliferation and cancer cell-stroma interactions. We will evaluate the effects of RB loss of function on TGF-beta signaling, assess the role of TGF-beta signaling in PDAC metastasis, and delineate the contributions of inflammatory cytokines and Wnt pathways to pancreatic cancer cell proliferation and stroma formation. To this end we will use cell lines established from KRC pancreata, use other novel GEMs of PDAC generated in our laboratory that exhibit a high incidence of metastases, conduct therapeutic interventions in these GEMs, and assess the role of these pathways in human PDAC. The proposed studies will advance our understanding of PDAC pathobiology in a high impact manner, and will point the way to novel therapies for suppressing cancer growth and metastasis.

Public Health Relevance

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer that is notoriously resistant to treatment, and the proposed plan to study novel aspects of PDAC in relation to abnormal mitogenic actions by transforming growth factor beta (TGF-beta) in the context of oncogenic Kras and retinoblastoma protein (RB) loss of function will greatly enhance our knowledge of this cancer. The proposal is relevant to public health because it is designed to delineate novel mechanisms that promote pancreatic cancer cell growth and metastasis, to evaluate the relevance of these mechanisms in relation to developmental and inflammatory signals, and to uncover novel therapies for suppressing pancreatic cancer cell proliferation and metastasis, which could then be translated into reduced morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA075059-16A1
Application #
8697384
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
1997-09-30
Project End
2019-04-30
Budget Start
2014-06-04
Budget End
2015-04-30
Support Year
16
Fiscal Year
2014
Total Cost
$441,940
Indirect Cost
$158,645
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Guo, Junchao; Kleeff, Jorg; Zhao, Yupei et al. (2006) Yes-associated protein (YAP65) in relation to Smad7 expression in human pancreatic ductal adenocarcinoma. Int J Mol Med 17:761-7

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