  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.
