Modelling of the multicellular tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on a fit-for-purpose biochip for preclinical drug discovery.

in Lab on a chip by Alina Deipenbrock, Ben Eric Wilmes, Thomas Sommermann, Nader Abdo, Kyra Moustakas, Martin Raasch, Knut Rennert, Nicole E Teusch

TLDR

  • Scientists developed a biochip platform to study pancreatic cancer and tested a Histone deacetylase inhibitor, showing it reduces tumor growth and modulates immune cell responses.
  • The platform allows for dynamic administration of drugs and immune cells, mimicking real-world conditions and providing insights into novel therapeutic strategies.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer. One major cause for a fast disease progression is the presence of a highly fibrotic tumor microenvironment (TME) mainly composed of cancer-associated fibroblasts (CAF), and various immune cells, especially tumor-associated macrophages (TAM). To conclusively evaluate drug efficacy, it is crucial to developmodels that can recapitulate the cross talk between tumor cells and the surrounding stroma. Here, we constructed a fit-for-purpose biochip platform which allows the integration of PDAC spheroids (composed of PANC-1 cells and pancreatic stellate cells (PSC)). Additionally, the chip design enables dynamic administration of drugs or immune cellsa layer of human umbilical vein endothelial cells (HUVEC). As a proof-of-concept for drug administration, vorinostat, an FDA-approved histone deacetylase inhibitor for cutaneous T cell lymphoma (CTCL), subjectedcontinuous flow for 72 h, resulted in a significantly reduced viability of PDAC spheroids without affecting vascular integrity. Furthermore, dynamic perfusion with peripheral mononuclear blood cells (PBMC)-derived monocytes resulted in an immune cell migration through the endothelium into the spheroids. After 72 h of infiltration, monocytes differentiated into macrophages which polarized into the M2 phenotype. The polarization into M2 macrophages persisted for at least 168 h, verified by expression of the M2 marker CD163 which increased from 72 h to 168 h, while the M1 markers CD86 and HLA-DR were significantly downregulated. Overall, the described spheroid-on-chip model allows the evaluation of novel therapeutic strategies by mimicking and targeting the complex TME of PDAC.

Overview

  • The study aimed to develop a biochip platform to evaluate drug efficacy in pancreatic ductal adenocarcinoma (PDAC) by recapitulating the tumor microenvironment (TME).
  • The platform integrates PDAC spheroids, cancer-associated fibroblasts, pancreatic stellate cells, and human umbilical vein endothelial cells.
  • The study tested the platform with vorinostat, a histone deacetylase inhibitor, and demonstrated its efficacy in reducing PDAC spheroid viability without affecting vascular integrity.

Comparative Analysis & Findings

  • The study showed that dynamic perfusion with peripheral mononuclear blood cells (PBMC)-derived monocytes led to immune cell migration and differentiation into macrophages.
  • The macrophages polarized into the M2 phenotype, as evidenced by increased expression of CD163 and decreased expression of CD86 and HLA-DR.
  • The polarization persisted for at least 168 hours, demonstrating the feasibility of the spheroid-on-chip model for studying immune cell function in PDAC TME.

Implications and Future Directions

  • The spheroid-on-chip model provides a valuable tool for evaluating novel therapeutic strategies targeting the TME in PDAC.
  • Future studies could explore the optimal timing and frequency of immune cell administration, as well as the combinatorial effects of immunotherapy with chemotherapy or other treatments.
  • The model could also be used to investigate the role of various immune cells and their interactions with tumor cells and stroma, enabling the development of more effective and targeted immunotherapies.
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