Functional analysis of the tumor suppressor gene FBXW7 in colorectal cancer progression and metastasis

• Applicant: Dr. Rene-Filip Jackstadt
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466506305

Cancer is driven by accumulation of genomic alterations in epithelial cells. The spectrum of these mutations has comprehensively been described by sequencing approaches and leveraged our understanding of cancer development and progression significantly. Deep mechanistic understanding of frequently detected alterations will eventually permit better treatment of colorectal cancer (CRC) patients. This is mainly of need for patients presenting with late stage CRC (III-IV), for which currently available treatments show only minimal efficacy (<10% survival in 5-years). For most late stage patients with solid tumors metastasis is the major cause of lethality. Better understanding of factors, which favor metastatic spread, will allow for improved targeted treatment and stratification. Previously, we have demonstrated that in epithelial cells NOTCH1 signaling plays a crucial role to drive CRC metastasis. However, the mechanisms of NOTCH pathway activation in CRC is fragmented. Interestingly, NOTCH pathway activating mutations are rarely detected in CRC, however, NOTCH receptors are marked for degradation by the recurrently mutated tumor suppressor FBXW7 (~20% mutated cases in CRC). Hence, loss of functional FBXW7 might depict a critical mechanism for NOTCH signaling activation. Here, we aim to determine the functional role of FBXW7 and its effectors in CRC progression and metastasis with the following strategies: i) manipulation of Fbxw7 (knock out and point mutation) in three state-of-the-art genetically engineered mouse models (GEMMs) and human CRC derived organoids with matching genetics. Notably, these models recapitulate the two major molecular routes to CRC (classical and serrated). ii) We will functionally investigate the capacity of NOTCH signaling as a downstream effector of FBXW7 phenotypes and its applicability as therapeutic target. iii) With the use of multi-omics analyses (transcriptome and proteome) FBXW7-dependent processes will be uncovered. These processes and FBXW7 substrates will be functionally validated with a particular focus on mechanisms of non-cell autonomous FBXW7 mediated tumor microenvironment rewiring. iv) Omics data from iii will be positioned to human CRC subtypes and FBXW7 targets will be validated in patient cohorts allowing us to describe the effect on recurrence and metastasis to facilitate clinical translation of our results. In sum, we set out to define the functional role of FBXW7 and identify downstream mediators in CRC progression and metastasis, which will open avenues for stratified treatment options for patients with late stage CRC.

• DFG Programme: Research Grants