Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer invasion via extracellular signal-regulated kinase 2

TL;DR

This study investigates how substrate stiffness influences the architecture of cancer-associated fibroblast-derived matrices in pancreatic cancer, revealing potential therapeutic strategies to reprogram the tumor microenvironment and inhibit tumor invasion.

Contribution

It demonstrates that substrate stiffness modulates matrix architecture, suggesting reprogramming desmoplasia or targeting ERK2 as novel therapeutic approaches for pancreatic cancer.

Findings

Matrix architecture can be manipulated via substrate stiffness.

Reprogramming desmoplasia may create tumor-restrictive environments.

Targeting ERK2 could inhibit pancreatic cancer invasion.

Abstract

Only about 8 percent of patients with pancreatic ductal adenocarcinoma, PDAC, live up to 5 years following diagnosis; by 2020 PDAC will become the second most lethal cancer in the United States. PDAC includes an anisotropic fibrous-like stroma, desmoplasia, encompassing most of the tumor mass. Desmoplasia is produced by cancer-associated fibroblasts, CAFs, and their cell-derived extracellular matrices, CDMs. Since elimination of CAFs is detrimental to patients, CDM reprogramming, as opposed to desmoplasia ablation, is therapeutically desirable. In this study we used a human mimetic three-dimensional CAF producing CDM system and proceeded to study its dynamic architectural modifications, following underlying substrate stiffness alterations, using digital imaging analyses, atomic force microscopy, mathematical modeling, cell biology, biochemistry and human tissue quantitative simultaneous multiplex immunofluorescence. Results suggested that the architecture of CDMs can be manipulated to render a tumor-suppressive microenvironment. We posit that perhaps treatments that could reprogram desmoplasia to become tumor-restrictive or that could target tumoral ERK2 might provide future new means for treating PDAC patients.