Thesis defended on December 3, 2025 to obtain the degree of Doctor of the Université Grenoble Alpes
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis, characterized by a progressive increase in nerve density from early lesions to invasive cancer. Among these, adrenergic nerves actively promote tumor progression, underscoring the need to understand their origin within the tumor microenvironment (TME) to enable nerve-targeted therapies. Murine models have identified a process termed tumor- induced neurogenesis, in which neural progenitor cells (NPCs) from the subventricular zone of the central nervous system (CNS) are recruited to distant tumor sites, where they differentiate into adrenergic neurons that promote tumor development. While the sequence of cellular events is well described in mice, the molecular signals mediating CNS-TME communication remain poorly understood, and whether this mechanism occurs in human PDAC is unknown. The aim of this thesis was to determine whether PDAC can attract CNS-derived NPCs and to assess the biological significance of this phenomenon in human disease. To this end, we developed complementary in vitro models. We generated and characterized human induced pluripotent stem cell-derived NPCs, which expressed canonical markers and retained neurogenic potential, and established spheroid models of pancreatic cancer cell lines and non-tumorigenic pancreatic ductal cells. Using Transwell assays, we showed that NPCs migrate robustly in response to defined growth factors. Conditioned media from pancreatic cancer cell lines similarly induced NPC migration, with stronger effects correlating with tumor aggressiveness. Cytokine profiling revealed that aggressive PDAC secretomes were enriched in chemokines, growth factors and extracellular matrix modulators, highlighting a network of inflammatory and matrix- remodeling signals likely involved in NPC attraction. To better mimic physiological gradients, we used organ-on-a-chip platforms and developed 3D co-culture models to study direct interactions between pancreatic cancer cells and NPCs. Finally, to assess the in vivo relevance of tumor-induced neurogenesis, we analyzed PDAC surgical specimens by immunofluorescence and identified cells co-expressing NPC markers along with adrenergic nerve markers, suggesting the occurrence of adrenergic differentiation events within the PDAC TME. In summary, this work establishes human models to study NPC-PDAC interactions, identifies candidate chemotactic signals secreted by aggressive pancreatic cancer cells that attract NPCs, and provides the first evidence of NPC-like cells in human PDAC tissues. These findings open new perspectives for therapeutic strategies targeting the neural niche of PDAC to limit tumor progression.