Pancreatic ductal adenocarcinomas (PDA) are unrivaled in their lethality. PDAs have the highest 1- year, 5-year, and 10-year mortalities of any cancer and are expected to become the second-leading cause of cancer-related death by 2030. An invasive PDA represents the coordinated evolution of cell- intrinsic and extrinsic processes and capabilities that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster unbridled growth and colonization. This new organizational entity is constructed at the behest of the mutated epithelial cell. The resulting PDA neo- organ contains a minority of tumor epithelial cells amidst a heterogeneous sea of non-epithelial cells; a complex interstitial stew of proteins, proteoglycans and glycosaminoglycans, together with both freely mobile and complexed water; and a paucity of vessels that otherwise resemble a normal vasculature in lacking fenestrae or interendothelial junctions, but that are collapsed under intense interstitial fluid pressures. We have undertaken a systematic exploration of the cell autonomous and non-cell autonomous processes that drive PDA pathogenesis and resistance. We have developed genetically engineered animal models that faithfully recapitulate the clinical syndrome, metastatic behavior, histopathology and molecular features of the human disease as primary platforms to both uncover critical principles of disease biology and to rigorously test strategies to overcome them. Through such investigations we have identified unusually high concentrations of intratumoral hyaluronan (HA) as the primary culprit in the extraordinarily elevated interstitial fluid pressures (IFP) in PDA that, in turn, cause the vascular collapse and hypoperfusion characteristic of this disease. The stromal barrier to perfusion also serves as a primary mechanism of drug resistance in limiting the tumor penetration of systemically delivered agents. We have additionally identified multiple mechanisms of immune suppression that prevent the development of an endogenous effector T cell response. Collectively, these unique aspects of stromal biology in PDA conspire to create a drug- and immune-privileged sanctuary for unimpeded growth of the pancreas cancer cell. Very recently, we have elaborated strategies to overcome critical aspects of these physical and immunological barriers to therapy revealing a perhaps unexpected degree of vulnerability once the barriers are breached. We describe a series of continuing investigations into this strategy of stromal re-engineering to expand upon the significant inroads made in the hopes of radically transforming the approach and prognosis for this formidable disease.

Public Health Relevance

Pancreas cancer kills every patient it afflicts and is now the fourth leading cause of cancer-related deaths in this country with a rising incidence and unabated mortality. We have developed genetically engineered animal models of pancreas cancer that have exposed unique points of vulnerability for the development of new treatments. We propose a systematic program of investigation to target distinct components of the stromal reaction in pancreas cancer as the basis for new treatment strategies against this highly resistant disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Fred Hutchinson Cancer Research Center
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Farr, Navid; Wang, Yak-Nam; D'Andrea, Samantha et al. (2018) Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: a pre-clinical study in a genetic model of pancreatic cancer. Int J Hyperthermia 34:284-291
Puré, Ellen; Hingorani, Sunil R (2018) Mesenchymal Cell Plasticity and Perfidy in Epithelial Malignancy. Trends Cancer 4:273-277
Stromnes, Ingunn M; Hulbert, Ayaka; Pierce, Robert H et al. (2017) T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma. Cancer Immunol Res 5:978-991
Whittle, Martin C; Hingorani, Sunil R (2017) Runx3 and Cell Fate Decisions in Pancreas Cancer. Adv Exp Med Biol 962:333-352
Whittle, Martin C; Hingorani, Sunil R (2017) Understanding Disease Biology and Informing the Management of Pancreas Cancer With Preclinical Model Systems. Cancer J 23:326-332
DuFort, Christopher C; Hingorani, Sunil R (2016) Tension and Transformation in Pancreas Cancer: Can Phenotype Break Free from the Chrysalis of Genotype? Cancer Cell 29:780-782
DuFort, Christopher C; DelGiorno, Kathleen E; Hingorani, Sunil R (2016) Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma. Gastroenterology 150:1545-1557.e2
DuFort, Christopher C; DelGiorno, Kathleen E; Carlson, Markus A et al. (2016) Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase. Biophys J 110:2106-19
Whittle, Martin C; Hingorani, Sunil R (2016) RUNX3 defines disease behavior in pancreatic ductal adenocarcinoma. Mol Cell Oncol 3:e1076588
Whittle, Martin C; Hingorani, Sunil R (2015) Disconnect between EMT and metastasis in pancreas cancer. Oncotarget 6:30445-6

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