Thesis presented March 17, 2023

Abstract:
At the time of diagnosis of pancreatic cancer, 40-65% of patients have diabetes. In recent years, mechanisms observed in markers type 2 diabetes hallmarks (hyperglycemia, insulin resistance and obesity) have been identified as potential risk factors for the development of pancreatic cancer. With a survival rate of 9% at 5 years, the increasing incidence and mortality of pancreatic cancer make it a major public health issue. A better understanding of the cellular and molecular mechanisms linking these two pathologies could help in the discovery of new biomarkers and even new therapeutic targets for the pancreatic cancer.
In this way, this PhD project aims at studying the role of the diabetic microenvironment on pancreatic tumor initiation. From human adipose tissue samples, a biocompatible hydrogel for cell culture in 3-dimensions has been developed. This hydrogel called atdECM (adipose tissue decellularized extracellular matrix) allows to model a human microenvironment. For this purpose, each step of the process (decellularization, delipidation, lyophilization, grinding and enzymatic digestion) was developed and optimized. A set of tests was established to allow the characterization of the biochemical and biomechanical properties of this hydrogel. Thus, atdECM, rich in growth factors and cytokines, has been shown to be permissive to the 3D culture of pancreatic and prostate cells. It also improves the survival of pancreatic endocrine pseudo-islet and maintains their functionality over several weeks. Finally, this hydrogel allows the differentiation of adipose stem cells into insulin-producing cells.
Thus, this matrix offers many possible applications, including the development of human pathophysiological cellular models as well as for its future use in personalized and regenerative medicine.

Keywords:
Diabetes, Decellularization, Microenvironment, Pancreatic cancer, Extracellular matrix, Adipose tissue