Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma

Graphical abstract

Tumor tissue stiffening drives tumor development, physiology, and poor drug perfusion. Tumor stiffness in PDAC is central to the disease aggressiveness, chemotherapeutic resistance, and the poor prognosis observed. It is important 3D in vitro models reflects the microenvironment and mechanical characteristic of the PDAC tissue to accurately develop and assess potential therapeutics and improve patient survival.

Highlights

• •

  The PDAC stroma stiffness underlines its malignant behavior and drug resistance.

• •

  3D in vitro cultures must model the PDAC stroma to effectively drug efficacy.

• •

  PSCs are responsible for the stroma, and its activity is increased with TGF-β.

• •

  Develop a 3D culture model of PDAC, which includes PSCs and TGF-β.

• •

  Assess the mechanical stiffness, stain for collagen, and investigate gemcitabine efficacy.

Abstract

Despite improvements in the understanding of disease biology, pancreatic ductal adenocarcinoma (PDAC) remains the most malignant cancer of the pancreas. PDAC constitutes ∼95% of all pancreatic cancers, and it is highly resistant to therapeutics. The increased tissue rigidity, which stems from the rich fibrotic stroma in the tumor microenvironment, is central to disease development, physiology, and resistance to drug perfusion. Pancreatic stellate cells (PSCs) are responsible for overproduction of extracellular matrix in the fibrotic stroma, and this is exacerbated by the overexpression of transforming growth factor-β (TGF-β). However, there are few in vitro PDAC models, which include both PSCs and TGF-β or mimic in vivo-like tumor stiffness. In this study, we present a three-dimensional in vitro PDAC model, which includes PSCs and TGF-β, and recapitulates PDAC tissue mechanical stiffness. Using oscillatory shear rheology, we show the mechanical stiffness of the model is within range of the PDAC tissue stiffness by day 21 of culture and highlight that the matrix environment is essential to adequately capture PDAC disease. PDAC is a complex, aggressive disease with poor prognosis, and biophysically relevant in vitro PDAC models, which take into account tissue mechanics, will provide improved tumor models for effective therapeutic assessment.