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Sophia Coffy

Effect of microenvironment on pancreatic tumour development

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Published on 19 December 2024
Thesis defended on December 19, 2024 to obtain the degree of Doctor of the Université Grenoble Alpes.​

Abstract :
Pancreatic ductal adenocarcinoma (PDAC) is a particularly aggressive cancer with one of the lowest survival rates five years after diagnosis. This poor prognosis is due to late diagnosis on one hand, and to the lack of efficacy of current chemotherapy-based treatments on the other hand. PDAC is characterized by marked heterogeneity at molecular and histological levels, with a diversity of subtypes and variants associated with variable patient prognoses. Patient-derived tumoroids represent a promising tool for developing preclinical models that consider tumor heterogeneity. However, faithful reproduction the tumor microenvironment in vitro remains a major challenge. PDAC is marked by a particularly high proportion of stroma, consisting mainly of an extracellular matrix produced by cancer-associated fibroblasts. In addition, the tumor microenvironment suffers from disorganization of vascular compartment. The complex, bidirectional interactions between tumor cells and their microenvironment appear to play an essential role in tumor progression and response to treatment, but these mechanisms remain poorly understood. Thus, the integration of this microenvironment into in vitro models appears crucial to improve the faithful representation of the tumor. In this context, we developed an in vitro cellular model that reproduces the complexity of the PDAC, by recapitulating the interactions between cancerous epithelial cells, endothelial cells and fibroblasts. Recent advances in the generation of decellularized extracellular matrices offer new prospects for the engineering of biological models. The decellularization process removes cellular components while preserving the matrix and soluble factors, thus recreating an environment close to the original extracellular matrix. In this context, a hydrogel derived from porcine pancreas extracellular matrix (pp-dECM) was developed. This hydrogel enabled the three-dimensional culture of pancreatic epithelial cells, promoting the formation of cell line-derived tumoroids as well as patient-derived tumoroids, in a similar way to Matrigel, commonly used for organoid culture. In addition, pancreatic fibroblasts and endothelial cells were cultured in pp-dECM hydrogel, resulting in the formation of self-organizing endothelial networks, comparable to those obtained with fibrin gel, used in this type of application. Preliminary results from the co-culture of pancreatic tumoroids with stromal cells revealed an influence of tumor cells on the organization of the endothelial network. In addition, a microfluidic device was developed to co-culture pancreatic tumor cells with elements of the tumor microenvironment, offering greater control over culture conditions and cell-cell interactions. This model represents a first step in the development of preclinical tools for testing therapeutic molecules to treat pancreatic tumors.​


Keywords :
organoids, pancreatic cancer, microfluidic chip, microenvironment​