Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma

•Shh-deficient tumors lacked stroma but were more aggressive and highly vascular•Differentiation status is plastic and may be dependent in part upon Hh signaling•Unlike differentiated tumors, undifferentiated PDAC is highly vascular•Undifferentiated pancreas tumors may be susceptible to VEGFR inhibition

SummarySonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation—features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.