Western-style diet induced cellular plasticity in early-onset colorectal cancer

• Applicant: Dr. Mark Schmitt
• Subject Area: Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550879831

Colorectal cancer (CRC) is traditionally associated with older age. However, recent epidemiological data suggest an alarming increase in CRC incidence diagnosed in the younger population, especially in industrialized countries. CRC in young adults display striking differences in their histological and molecular features when compared to CRC in the elderly, often coming along with more aggressive clinical behavior, suggesting that early-onset CRC (EO-CRC) and late-onset CRC (LO-CRC) are distinct tumor entities. Although, the contribution of environmental factors to the rise of EO-CRC is more and more recognized, the underlying cause for the profound molecular and clinicopathological differences between EO-CRC and LO-CRC are poorly understood. It is well accepted that a “western” lifestyle, especially western-style dietary habits, substantially contribute to the recent increase of CRC cases in young adults. Here, we propose that western-style diet (WSD) is furthermore to a huge extent responsible for the phenotypic differences between early-onset and late-onset colorectal tumors. More precisely, we hypothesize that WSD sets the course for a diverging developmental route of the tumor already at the very beginning of tumorigenesis: by altering its cell-type-of-origin. It is the general consensus that the origin of CRC resides in tissue resident stem cells, which are under physiological conditions represented by Lgr5 expressing cells at the base of the intestinal crypt. Strikingly, WSD strongly suppresses the proliferation and tumorigenic potential of these canonical Lgr5+ intestinal stem cells (Lgr5+ ISCs), while reprogramming committed intestinal epithelial cells to stem-like cells, thereby shifting the target of cancer initiating mutations from Lgr5+ ISCs to these alternate intestinal stem cell types (aISCs). As these usually more differentiated cells are less equipped to repair damaged DNA and show reduced sensitivity to DNA damage induced apoptosis, the switch from canonical Lgr5+ ISCs to aISCs, might not only influence the overall risk to develop CRC and accelerate tumorigenesis but also favor the development of distinct CRC subtypes with specific mutational signatures and distinct molecular and cellular characteristics. In order to address the relationship between WSD and EO-CRC, we will first employ CRC mouse models to examine in detail how CRCs diverge regarding their molecular, immunological and mutational characteristics when they derive from different cell-types-of-origin and in the context of WSD. We will then assess if WSD specific alterations, found in the murine tumors, resemble the distinct characteristics of human EO-CRC. Moreover, we will address how WSD the tumors' response to chemo- as well as immunotherapy in preclinical CRC mouse models and assess the potential of specific WSD-mediated tumor alterations as prognostic factors regarding patient prognosis and treatment response.

• DFG Programme: Research Grants