33 Context, background, aims, and outline of the thesis tion scheme. To achieve this, reliable C-terminal MET antibodies were identified (chapter 3), MET protein status was investigated through parallel use of reliable C- and N-terminal MET antibodies (chapter 4), and a sensible scoring system was designed for whole tissue sections (chapter 5). Eventually, the work performed to realize chapters 3-5, defined four MET staining patterns across cancer fields (uniform negative, gradient toward the periphery, uniform positive, and gradient toward the center), and stratified OSCC into three categories based on MET protein status: MET negative (no immunoreactivity), decoy MET (more positivity for the N-terminal moAb), and transmembranous C-terminal MET (equal positivity for both moAbs (complete MET), or more positivity for the C-terminal moAb (complete MET and/or membrane-bound MET lacking the ectodomain (MET-EC-))). Additionally, the prognostic value of C-terminal immunoreactivity and MET-EC- was established (chapters 3 through 5). Ultimately, a proposed patient stratification scheme for MET targeted therapies, specifically moAbs and tyrosine kinase inhibitors (TKIs), was designed incorporating MET protein status (chapters 4, 5). Having established that C-terminal MET uniform positivity is associated with poor overall and disease-free survival in OSCC and knowing that MET is an orchestrator of invasive growth, it was investigated and confirmed that C-terminal MET uniform positivity is associated with the presence of RLNM (pN+ and occult) in early OSCC. Since C-terminal MET uniform positivity outperforms DOI, it potentially has added value in the preoperative setting concerning the clinical decision to perform an END during the initial surgery. Alternatively, for OSCC with DOI ≤ 4 mm, C-terminal MET uniform positivity could aid in the clinical decision whether regular follow-up, watchful waiting, or END is more appropriate (chapter 6). Ultimately, it is proposed that MET-EC- confers malignant potential to OSCC and that ectodomain shedding should be implemented in the design of CDx to improve the success rate of MET targeted therapies (chapter 7). The work performed in, results obtained from, and coherence between chapters 3 through 7, are summarized in Figure 2. After chapter 7, we elaborate on the obtained results, drawn conclusions, gained insights, and future perspectives developed while compiling this thesis in the general discussion (Chapter 8). Finally, the context of the work performed in this thesis and the achieved results are summarized per chapter (Chapter 9). 2
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