Viscoelastic properties of human pancreatic tumors and in vitro constructs to mimic mechanical properties

摘要

Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal, in large part due to a protective fibrotic barrier generated by tumor-associated stromal (TAS) cells. This barrier is thought to promote cancer cell survival and confounds attempts to develop effective therapies. We present a 3D in vitro system that replicates the mechanical properties of the PDAC microenvironment, representing an invaluable tool for understanding the biology of the disease. Mesoscale indentation quantified viscoelastic metrics of resected malignant tumors, inflamed chronic pancreatitis regions, and histologically normal tissue. Both pancreatitis (2.15 ± 0.41 kPa, Mean ± SD) and tumors (5.46 ± 3.18 kPa) exhibit higher Steady-State Modulus (SSM) than normal tissue (1.06 ± 0.25 kPa; p < 0.005). The average viscosity of pancreatitis samples (63.2 ± 26.7 kPa·s) is significantly lower than that of both normal tissue (252 ± 134 kPa·s) and tumors (349 ± 222 kPa·s; p < 0.005). To mimic this remodeling behavior, PDAC and TAS cells were isolated from human PDAC tumors. Conditioned media from PDAC cells was used to culture TAS-embedded collagen hydrogels. After 7 days, TAS-embedded gels in control medium reached SSM (1.45 ± 0.12 kPa) near normal pancreas, while gels maintained with conditioned medium achieved higher SSM (3.38 ± 0.146 kPa) consistent with tumors. Taken together, we have demonstrated an in vitro system that recapitulates in vivo stiffening of PDAC tumors. In addition, our quantification of viscoelastic properties suggests that elastography algorithms incorporating viscosity may be able to more accurately distinguish between pancreatic cancer and pancreatitis.