Modeling biophysical tumor-stroma interactions in 3D co-cultures of pancreatic cancer cells and pancreatic stellate cells

Mechanical interactions between tumor cells and stromal components impact cancer progression and therapeutic response. Tumors of the pancreas in particular are associated with stiff fibrous stroma impacting growth and drug delivery. Here we use time lapse imaging to study contractile force mediated by adhesions between pancreatic ductal adenocarcinoma (PDAC) cells and pancreatic stellate cells (PSCs), a fibroblastic stromal signaling partner, in 3D culture on laminin rich extracellular matrix (ECM). PDAC cells overlaid on ECM form compact multicellular 3D nodules. When PSCs are introduced there is a profound change in growth behavior culminating in the formation of large connected structures mediated by contractile force of activated PSCs. We analyze this behavior using particle image velocimetry, as well as analysis of nodule size distribution. We use immunofluorescence to characterize the E-cadherin/N-cadherin adhesion in these co-cultures and show that E-cadherin deficient PDAC cells are unable to form adhesions with stromal cells and exhibit decreased contractility as a result. Going forward, we are leveraging this system to model and study drug delivery through fibrotic PDAC stroma and evaluate stromal depletion therapies.