E3 ubiquitin ligases as prognostic and predictive biomarkers in colorectal cancer

The aim of this project is to identify and functionally characterize E3 ubiquitin ligases involved in colorectal cancer pathogenesis and to evaluate their potential as prognostic and predictive biomarkers for this disease. Our research is focused on the E3 ubiquitin ligases RNF43 and NEDD4:

RNF43

Dysregulation of the WNT pathway is a common characteristic of nearly all colorectal cancers. The E3 ubiquitin ligase, RNF43 (ring finger protein 43), and its paralog ZNRF3 (zinc and ring finger 3), play a critical role in controlling the abundance of WNT receptors at the cell surface, by catalyzing their ubiquitination and thereby targeting them for endolysosomal degradation. By reducing the levels of WNT receptors at the cell surface, RNF43/ZNRF3 negatively regulate the intensity and duration of WNT signaling. RNF43 mutations are found in several cancers, including colorectal cancer. A recent retrospective study found that the benefit from targeted combination treatment of metastatic, microsatellite stable (MSS) colorectal cancer with the BRAFV600E mutation was substantially higher in patients who, in addition, had inactivating mutations in RNF43 (Elez, E. et al. Nat. Med., 2022). RNF43 mutation is the only biomarker that has been proposed to predict response to anti-BRAF/EGFR therapy. However, the molecular mechanisms underlying this observation are largely unknown.

In this project, we combine functional and pharmacological studies of RNF43, using as a model system patient-derived organoids (PDOs) derived from liver metastases of patients with colorectal cancer. The project is carried out in close collaboration with the project groups led by Kushtrim Kryeziu and Anita Sveen.

NEDD4

NEDD4 (neural precursor cell expressed developmentally down-regulated protein 4) is the founding member of the NEDD4 family of E3 ubiquitin ligases, which consists of nine members in humans. NEDD4 is a proto-oncogene, and in most cancer types its oncogenic activity has been attributed to its ability to mediate the ubiquitination and degradation of the tumor suppressor protein PTEN (protein phosphatase and tensin homolog). Our lab was the first to show that NEDD4 displays oncogenic properties in colorectal cancer (Eide, P.W. et al., Cell. Signal., 2013). In our ongoing studies, we are aiming at obtaining a better understanding of the molecular basis by which NEDD4 promotes colonic cell growth and its potential as a biomarker in colorectal cancer.

 
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