Thèse Décryptage du Rôle de la Mécanotransduction dans la Reprogrammation des Macrophages dans le Cancer du Pancréas H/F - Doctorat.Gouv.Fr

Établissement : Université Claude Bernard Lyon 1 École doctorale : CanBioS - Cancérologie, Biologie, Santé de Lyon Laboratoire de recherche : CRCL - CENTRE DE RECHERCHE EN CANCÉROLOGIE DE LYON Direction de la thèse : Ana HENNINO ORCID 0000000226198559 Début de la thèse : 2026-10-01 Date limite de candidature : 2026-05-11T23:59:59 Pancreatic ductal adenocarcinoma (PDAC), which has an overall survival rate of 2-9%, is currently the fourth leading cause of cancer related deaths in the industrialized world and it is predicted to become the second leading cause by 2030. The deposition of this massive stroma has now emerged as a critical actor and contributor in pancreatic tumor initiation and progression. Three major factors are crucial in the establishment of stromal reaction: the tumor-derived components, the local microenvironment (in particular the fibroblasts) of the host, and the bone-marrow-derived cells (in particular the macrophages). These 3 partners are key in the establishment of the 'stromal niche' in the primary tumor site.
Amongst the stromal proteins, ig-h3 (also known as TGFBI) is of the utmost interest as it has been shown that its overexpression in the stroma is of bad prognosis in PDAC. Along this line, Ana Hennino (co-supervisor) explored the potential role of the TGFBI stromal protein using the PDAC model (both in mice and humans) and have determined its mechanism of action, promoting the evolution of the disease: the presence of this protein (i) decreases the cytotoxic activity of CD8+ T lymphocytes and (ii) helps stiffen the microenvironment, making the tumor less accessible to the immune system. At the genesis of this project was the observation that TGFBI regulates Notch signaling. The role of Notch signaling in PDAC is quite paradoxical. Indeed, Notch1 was described as a tumor suppressor, whereas Notch was described as an oncogene. An important limitation of most published studies on the role of Notch signaling in PDAC is the fact that they exclusively focused on the epithelial compartment, manipulating Notch signaling under the control of epithelial promoters. However, it is now recognized that Notch signaling should be thoroughly studied by manipulating specific compartments in the tumor microenvironment. More recently, Notch signaling has been shown to regulate macrophages M2 phenotype in PDAC. Olivier Meurette (co-supervisor) has extensive expertise in Notch signaling, showing that heterotypic interaction in the stroma are important.
However, how TGFBI accumulation globally impacts both the physical properties of tumors and mechanosensitive pathways in the PDAC TME needs further investigations. Additionally, it is still unclear how therapeutically modifying the stroma reshapes mechanosensitive pathways, possibly leading to resistance mechanisms. Moreover, studying these pathways requires specific setups in which physical properties are conserved, as well as cell-cell and cell-matrix contacts. This project thus relies on the merging of very different approaches and will capitalize on the different expertise and skills of the two co-supervisors.
The project will be articulated around 3 axis.
Axis 1. Characterize in a targeted approach the tri-party crosstalk between cancer cells, CAFs, and macrophages.
Axis 2. Assess the overall forces and mechanotransduction pathways in complex PDAC organoids to identify specific tumor mechanotransduction signatures.
Axis 3.Topography of mechanical properties and cell signaling in pancreatic cancer.
ce projet s'incrit dans le cadre du projet scientifique dans le laboratoire qui explore les interactions paracrines entre les macrophages et CAF dans le cancer solide en particulier dans le cancer du pancreéas

master cancer