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

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.

Multimodal Therapies against Pancreatic Ductal Adenocarcinoma: A Review on Synergistic Approaches toward Ultimate Nanomedicine Treatments

“…Cancer applications include I) the incorporation of multiple cell types, like those typically present in the TME, to allow the study of the interactions between cancer cells and surrounding tissues, II) the modeling of microvascular networks to assess antiangiogenic drugs and study tumor vascular perfusion; III) the study of cancer cells' extravasation and migration to induce metastasis formation. [664] Due to their ability in recapitulating the microenvironments of in vivo tissues, OOC models have been applied to pancreatic cancer with the final aim of providing a complex multicellular model of human PDAC on a chip, designed for drugs and therapeutics testing. One of the first applications included an in vitro model consisting of pancreatic stellate cells cocultured with PDAC cells in an accessible 3D construct with a spatially controlled architecture, which was proposed as an alternative platform for drug evaluation.…”

“…Cancer applications include I) the incorporation of multiple cell types, like those typically present in the TME, to allow the study of the interactions between cancer cells and surrounding tissues, II) the modeling of microvascular networks to assess antiangiogenic drugs and study tumor vascular perfusion; III) the study of cancer cells’ extravasation and migration to induce metastasis formation. [ 664 ]…”

Microfluidic Platforms for High-Throughput Pancreatic Ductal Adenocarcinoma Organoid Culture and Drug Screening

“…Thus, a preliminary sequencing of the DNA of patients and mutation status could give an indication of the type of drugs that should be tested on organoids and afterwards prescribed to a given patient. Moreover, Haque et al recently discussed the impact of the heterogenous TME in PDAC and concluded that extensive model development is still needed for establishing efficient drug pipelines ( Haque et al, 2021 ). Therefore, current in vitro model systems are lacking in translational value, and novel PDAC models that allows for rapid initial drug testing that provide a truly translational outcome for identifying novel patient treatment options are called for.…”

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

“…16 For these reasons, current research is focusing on the development of in vitro PDAC models for a deeper understanding of this pathology, the identification of new biomarkers and the establishment of screening tests, in order to enable the earlier detection of pancreatic cancer and improve the prognosis. [17][18][19][20][21][22] However, one of the major limitations of PDAC in vitro models is the difficulty in replicating the tumor microenvironment surrounding the gland and the PDAC-stroma crosstalk, which constitutes an important feature that significantly affects tumor evolution and drug resistance. [22][23][24][25][26] Among the existing in vitro models, organ-on-achip microfluidic systems represent a powerful tool to reproduce the cancer cell-stroma interactions in a controllable environment and under real-time monitoring.…”