Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Γεώργιος Κόλλιας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μιχαήλ Κουτσιλιέρης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Βασιλική Κολιαράκη, Ερευνήτρια B’, Ινστιτούτο Βασικής Έρευνας, Ε.ΚΕ.Β.Ε. «Αλέξανδρος Φλέμιγκ»
Κλειώ Μαυραγάνη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αντώνιος Χατζηγεωργίου, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Παληκαράς, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μιχάλης Βερυκοκάκης, Ερευνητής Γ’, Ινστιτούτο Βασικής Έρευνας, Ε.ΚΕ.Β.Ε. «Αλέξανδρος Φλέμιγκ»
Original Title:
Identification of mesenchymal specific pathways in intestinal carcinogenesis
Translated title:
Identification of mesenchymal specific pathways in intestinal carcinogenesis
Summary:
Colorectal cancer (CRC) ranks as the third most prevalent cancer and a leading cause of global cancer-related mortality. Beyond the focus on cancer cells, it is now widely acknowledged that the tumor microenvironment (TME) significantly influences the initiation and progression of CRC. A pivotal component of the TME is the cancer-associated fibroblasts (CAFs), which play indispensable roles in the development and advancement of cancer. Despite recent advances in understanding CAF heterogeneity, a comprehensive understanding of their diverse origins, properties, and functions remains elusive. This thesis focuses on the intricate aspects of CAF origin, elucidating their physiological roles and investigating downstream pathways that orchestrate intestinal tumorigenesis.
By employing the Col6a1Cre mouse, we successfully targeted a distinct CAF population in two mouse models of intestinal carcinogenesis. Col6a1+ CAFs maintained key homeostatic characteristics, while they also became activated, supporting CAFs’ origin from resident populations. Both bulk and single cell RNA sequencing showed that Col6a1+ CAFs were mainly pericytes/vCAFs and to a lesser extent PDGFRahi-like fibroblasts, in accordance with the significant expansion of vCAFs in colon tumors. Both in vitro and in vivo experiments showed that Col6a1+ CAFs had pro-tumorigenic roles, as they could support tumoroid growth in co-cultures and xenograft growth. Mechanistically, Col6a1+ IMCs responded to innate immune stimuli in vitro and produced inflammatory mediators, including cytokines, chemokines, and ECM remodeling enzymes. In vivo, TLR4/Myd88 innate sensing by the Col6a1+ CAF population was essential for the Apc driven tumorigenesis but indispensable for colitis-induced cancer development. The findings contribute to advancing our knowledge of CAF heterogeneity and highlight the role of innate immune sensing as a driver of CAF activation in colorectal cancer.
Main subject category:
Health Sciences
Keywords:
Cancer associated fibroblasts, Intestinal fibroblasts, Tumor microenvronment, Colorectal cancer
Number of references:
394
