A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a complex, heterogeneous, and genetically unstable disease. Its tumor microenvironment (TME) is complicated by heterogeneous cancer cell populations and strong desmoplastic stroma. This complex and heterogeneous environment makes it challenging to discover and validate unique therapeutic targets. Reliable and relevant in vitro PDAC tumor models can significantly advance the understanding of the PDAC TME and may enable the discovery and validation of novel drug targets. In this study, an engineered tumor model is developed to mimic the PDAC TME. This biomimetic model, named ductal tumor‐microenvironment‐on‐chip (dT‐MOC), permits analysis and experimentation on the epithelial–mesenchymal transition (EMT) and local invasion with intratumoral heterogeneity. This dT‐MOC is a microfluidic platform where a duct of murine genetically engineered pancreatic cancer cells is embedded within a collagen matrix. The cancer cells used carry two of the three mutations of KRAS, CDKN2A, and TP53, which are key driver mutations of human PDAC. The intratumoral heterogeneity is mimicked by co‐culturing these cancer cells. Using the dT‐MOC model, heterogeneous invasion characteristics, and response to transforming growth factor‐beta1 are studied. A mechanism of EMT and local invasion caused by the interaction between heterogeneous cancer cell populations is proposed.

The Revolutionary Roads to Study Cell–Cell Interactions in 3D In Vitro Pancreatic Cancer Models

“…One of the main advantages of using microscopy-based imaging approaches is the ability to observe spatial relations among different cell types with high temporal resolution under physiological conditions [ 73 ]. In this scenario, in vitro PDAC-on-a-chip provides powerful platforms to study the microenvironment of PDAC since these devices allow imaging of cell–cell interactions, such as tumor–endothelial and tumor–immune cell interactions, as well as cell morphological changes, by applying different types of fluorescence microscopy techniques [ 4 , 74 , 75 , 76 , 77 , 78 ]. In a recent work by Hye-ran Moon et al, a microfluidic pancreatic tumor model was developed, recapitulating the heterogeneous driver mutations of human PCs by using PDAC cells derived from genetically engineered mouse models (KPC with Kras and Trp53 mutations, and KIC with Kras mutation and Cdkn2a deletion) in order to mimic the intra-tumoral heterogeneity ( Figure 4 a) [ 77 ].…”

“…( f ) Representative immunofluorescence image of 3D bioprinted tissues for PDAC (green), PSC (red), and endothelial (yellow) cells (adapted from [ 68 ]). ( g ) IF image of the invasion of a heterogeneous co-culture of PDAC cells (adapted from [ 75 ]).…”

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

“…PDAC is a complex, heterogeneous, and genetically unstable disease (7) with undetermined developmental and metastatic mechanisms. PDAC is thought to arise from acinaductal metaplasia and develop into invasive carcinoma through pancreatic intraepithelial neoplasia lesions as key genetic mutations accumulate (8)(9)(10).…”

Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer

“…The tumor heterogeneity was reconstituted using pancreatic cancer cells from GEMM carrying KRAS, CDKN2A, and TP53 mutations, key driver mutations of human PDAC. This model revealed the complex interactions between cancerous epithelial cells in PDAC, leading them to be more aggressive and invasive [112].…”

“…Recent advancements of PDAC TME on chip models are summarized in Table 1. A biomimetic ductal TME on a chip, where ductal pancreatic cancer epithelium cells were surrounded by collagen matrix in the chip, recapitulated the histopathology of PDAC [112]. The tumor heterogeneity was reconstituted using pancreatic cancer cells from GEMM carrying KRAS, CDKN2A, and TP53 mutations, key driver mutations of human PDAC.…”