Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.

PDAC-on-chip for in vitro modeling of stromal and pancreatic cancer cell crosstalk

“…56,57 Although recent studies have shown the possibility of modeling the PDAC microenvironment in vitro , 17,20,28,33,34,58–61 the tumor-stroma crosstalk remains extremely challenging to reproduce and monitor in functionally effective models. 62–64…”

“…56,57 Although recent studies have shown the possibility of modeling the PDAC microenvironment in vitro, 17,20,28,33,34,[58][59][60][61] the tumor-stroma crosstalk remains extremely challenging to reproduce and monitor in functionally effective models. [62][63][64] We report herein the design, development and characterization of a multilayer PDAC-on-chip device to mimic the tumorstroma relationship through the culture of human pancreatic ductal epithelial cells expressing the activated KRAS and human pancreatic stellate cells, on the same miniaturized platform. In particular, the HPDE-KRAS cells and the PSCs were respectively seeded in the top and in the bottom layers, separated by an electrospun PCL/gel membrane.…”

Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids

“…One limitation of the used 3D spheroid model is the monoculture of PADC cells. In future studies this model can be further developed by coculturing cancer-associated fibroblasts and immune cells to improve resembling the characteristic dense stroma of PDACs [ 29 , 47 ].…”

3Din vitromodeling of the exocrine pancreatic unit using tomographic volumetric bioprinting

“…Therefore, the understanding of pancreatic cancer raises interests among the scientific community, currently developing efficient PDAC in vitro models in order to detect the disease earlier and design effective therapies thus improving patients' prognosis [23][24][25][26][27][28] . Although recent works have shown the possibility of modeling the PDAC microenvironment in vitro 23,24,26,[29][30][31][32][33][34] , the tumor-stroma interplay remains arduous to be replicate and monitor in functionally effective models [35][36][37][38] . Heterotypic 3D spheroids, patient-derived organoids, cancer-on-a-chip platforms, and 3D biofabricated constructs are the currently available bioengineered 3D models mimicking the pancreatic tumor-stroma interplay 16 .…”