Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.
Bibliographical noteFunding Information:
We thank Randi Simmons, Markus Carlson, and Simon Bennett for assistance with animal husbandry and care; Julie Randolph-Habecker and members of FHCRC Experimental Histopathology for assistance with histology and immunohistochemistry; and members of the Hingorani and Olson laboratories for helpful discussions. We thank Shelley Thorsen for expert assistance with figure and manuscript preparation, John Potter for helpful discussions and comments on the manuscript, and Gregory Frost and Michael Shepard for providing PEGPH20 and for helpful discussions. TMA sections were kindly provided by Galen Hostetter and Clifford Whatcott. D.D.V.H. has a consulting agreement with Halozyme Therapeutics. This work was supported by the National Cancer Institute (grants CA161112 and CA114028 to S.R.H., CA152249 to P.P.P. and S.R.H., and CA109552 to D.D.V.H.), the Giles W. and Elise G. Mead Foundation (support to S.R.H.), donated funds from David Jones and Maryanne Tagney-Jones (support to S.R.H.), donated funds from Safeway (support to S.R.H.), and a Jaconette L. Tietze Young Scientist Award (to P.P.P.).