Pancreatic cancer stroma: friend or foe?

Abstract

Pancreatic cancer desmoplasia is thought to confer biological aggressiveness. In this issue of Cancer Cell, Özdemir and colleagues and Rhim and colleagues demonstrate that targeting the stroma results in undifferentiated, aggressive pancreatic cancer that responds to checkpoint blockade or antiangiogenic therapy, uncovering a protective role by stroma in this cancer.

Figure 1. Deleterious Consequences of Targeting the Stroma in Pancreatic Cancer

(A) Highly desmoplastic PDAC. These tumors exhibit activated cancer-associated fibroblasts (CAFs) that synthesize and release collagens, laminin, and fibronectin (desmoplasia); are infiltrated by various inflammatory cells including macrophages (Macs); and produce excess growth factors and cytokines. Cancer cells in these lesions may be well, moderately, or poorly differentiated. (B) Stroma-depleted PDAC. Engineered myofibroblast (MFB) depletion, genetic deletion of sonic hedgehog (Shh), or Smoothened receptor targeting with IPI-926 were used to dramatically decrease the presence of MFBs and CAFs in several genetically-engineered mouse models (GEMMs) of PDAC. Each of these strategies yielded undifferentiated PDAC, enhanced EMT, increased pancreatic cancer cell proliferation, and altered immune cell infiltrate profiles. Direct MFB depletion was associated with attenuated angiogenesis and an increased response to immune checkpoint blockade with an anti-CTLA-4 antibody. Shh deletion or IPI-296 treatment was associated with increased angiogenesis (Endo) and metastasis, a greater incidence of cachexia, and increased responsiveness to DC101, which targets VEGFR2. Thus, in several GEMMs and with different strategies, targeting the stroma unmasks a previously unrecognized protective effect in PDAC.