Pancreatic cancer continues to have one of the highest mortality rates of any malignancy and the 5-year survival rate remains less than 5% largely because of its propensity for metastasis and drug resistance. These problems have not yet been overcome, but recent research indicates that there is great variability in the intrinsic potential among distinct subpopulations of tumor cells to metastasize or resist treatment; that pancreatic cancer cells are functionally heterogeneous. We and others identified several phenotypically distinct pancreatic cancer cell populations that are enriched in tumor-initiating capacity, defining them as cancer stem cells (CSCs). The aldehyde dehydrogenase (ALDH)-expressing CSC population is associated with worse clinical outcomes, resistant to chemotherapy, and has higher metastatic potential. The mechanisms that regulate the functional characteristics of CSCs as well as what regulates the balance between pancreatic CSCs and non-CSCs are poorly understood. Our recent research indicates that pancreatic CSCs are maintained by direct interactions with certain proteins in the tumor microenvironment (TME) and focal adhesion kinase (FAK) signaling. We hypothesize that the TME plays a critical role in regulating the equilibrium between CSCs and non-CSCs, and that specific signaling pathways activated by the TME regulate CSC functional characteristics. Using our groups' expertise we propose to: 1) Determine the role of specific extracellular matrix proteins and integrins on FAK activation and regulation of the equilibrium between CSC and non-CSCs, 2) Evaluate the role of FAK activation on tumor progression and CSC function in the genetically engineered Ptf1a-Cre; KrasG12D/+; p53R172H/+ (KPC) pancreatic cancer mouse model, 3) Determine the most effective clinical setting in which antagonists of FAK can inhibit pancreatic cancer growth and metastasis using in vivo models, and 4) Evaluate if FAK protein expression can predict response to therapy. These studies will enhance our understanding of mechanistic interactions with the TME that regulate pancreatic CSCs, and will guide the clinical development of novel CSC-directed therapies.

Public Health Relevance

Cancer stem cells (CSCs) are a subpopulation of cancer cells that have been shown to mediate metastasis and drug resistance and are associated more rapid disease progression in patients with pancreatic cancer. With a goal to better understand pancreatic CSC biology and to develop improved therapies for patients with pancreatic cancer, our lab has been studying how the tumor microenvironment affects pancreatic CSC maintenance and function. In this proposal we will investigate signaling pathways that regulate extracellular matrix-induced CSC maintenance and function, and develop therapeutic strategies to disrupt these critical interactions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Ault, Grace S
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Begum, Asma; Ewachiw, Theodore; Jung, Clinton et al. (2017) The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma. PLoS One 12:e0180181
Rich, Jeremy N; Matsui, William H; Chang, Jenny C (2016) Cancer stem cells: A nuanced perspective. Medicine (Baltimore) 95:S26-8
Matsui, William H (2016) Cancer stem cell signaling pathways. Medicine (Baltimore) 95:S8-S19
Gocke, Christian B; McMillan, Ross; Wang, Qiuju et al. (2016) IQGAP1 Scaffold-MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal. Mol Cancer Ther 15:2733-2739