Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

Abstract

The desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets. More recently, however, it has also become apparent that diverse subpopulations of fibroblasts with distinct phenotypes and secretomes inhabit the stroma, and that targeted depletion of particular fibroblast subsets could either provide substantial therapeutic benefit or accelerate disease progression. An improved characterization of these fibroblast subtypes, along with their potential relationships to tumor subtypes and mutational repertoires, is needed in order to make anti-fibroblast therapies clinically viable.

Keywords: Desmoplasia; Fibroblast; GEMM; PDA.

Figure 1.. Differential Hh signaling in αSMA+ and FAPα+ fibroblast subpopulations.

αSMA+/FAPα-fibroblasts are physically closer to PDA epithelia and likely have higher overall Hh signaling than αSMA-/FAPα+ fibroblasts due to greater exposure to epithelial-derived Hh ligand, lower expression of Ptch1/2 and higher expression of Smo. For these reasons, inhibitors of Smo, such as saridegib and vismodegib, may preferentially target this αSMA+/FAPα- fibroblast subpopulation.

Figure 2.. Effects of cardinal genomic alterations in PDA may disparately influence fibroblast context, function and heterogeneity.

Activating Kras mutation in pancreatic epithelial cells induces production of Il-6 and Shh, which help convert quiescent PSC to activated fibroblasts. Subsequent mutation of Trp53, loss of Smad4 and/or silencing of Cdkn2a in the neoplastic epithelium may differentially shape the ECM through distinct mechanisms of paracrine signaling to fibroblasts.

Figure 3.. MCN are characterized by unique fibroblast subpopulations.

A) Stromal fibroblasts in murine PanIN. B) Ovarian-type stromal fibroblasts with characteristic wavy nuclei (arrows) in murine MCN. C) Nuclear ER positivity (red) in fibroblasts of murine MCN.