254 Chapter 9 in OSCC cell lines and tissues using two reliable antibodies directed against the C- and N-terminus of MET in parallel, e.g. D1C2 and A2H2-3 (22) in chapter 4. Having established that MET degradation occurs in OSCC, D1C2 and A2H2-3 were again applied in parallel to determine MET protein status in an OSCC patient cohort using the same TMA as described in chapter 3. This allowed categorization of MET protein status into 3 groups: MET negative (no MET immunoreactivity), decoy MET (more positivity for A2H2-3), and transmembranous C-terminal MET (complete MET (equal positivity for both D1C2 and A2H2-3), or MET C-terminus lacking the ectodomain (more positivity for D1C2)). It was also established that MET ectodomain shedding is associated with poor disease free survival in OSCC positive for transmembranous C-terminal MET. Since more than half of the patient’s that are uniform positive for D1C2 (as defined in chapter 3) are subjective to ectodomain shedding, it might have an impact on the choice of therapy, i.e. moAb or TKI. Ultimately, a proposed CD was designed for the use of targeted therapies directed against MET. In chapter 4, TMAs were used to show and discuss that uniform positive D1C2 immunoreactivity and ECD shedding are associated with poor prognosis in OSCC. Seen the potential prognostic and predictive value, it is investigated in chapter 5 whether the TMA results can be extrapolated to WTSs. Here, a novel scoring system is presented that describes four staining patterns across cancer fields, namely uniform negative, uniform positive, gradient towards periphery, and gradient towards center. These staining patterns find their origin in the observed membranous D1C2 immunoreactivity described in chapter 3. Since MET is known to orchestrate EMT (23, 24), the results were benchmarked to loss of E-cadherin, a readout for EMT known to be associated with poor prognosis (25, 26). Aligning C- and N-terminal MET, as well as E-cadherin immunoreactivity, using the developed scoring system accounts for MET protein status, ECD shedding, and EMT. Moreover, it is prognostically informative for C-terminal MET positive cancers with respect to D1C2 uniform positivity, ECD shedding, and loss-of E-cadherin. The consistencies observed between chapter 4 and 5 in terms of outcome measures, led us to believe that our findings concerning C-terminal MET immunoreactivity and ECD shedding might support the development of CDx for MET targeted therapies that can be applied within a routine diagnostic setting. Having established that D1C2 uniform positivity is associated with poor OS and DFS in OSCC having overall more C- than N-terminal MET immunoreactivity, and knowing that MET is an orchestrator of invasive growth in OSCC, it was investigated whether C-terminal MET uniform positivity is associated with RLNM in early OSCC in chap-
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