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.