CApaCITy · CAncer Stem Cell Imunoreceptors as potential Targets for skin Squamous cell carcinoma

Cancer stem cells (CSC) initiate, sustain the prevalence, and resistance to therapy of skin squamous cell carcinomas (SCC). It is well acknowledged that CSC self-renewal and clonal growth is governed by genetic mutations, but also by complex interactions between CSC and the microenvironment. Genetic therapy is difficult to achieve in clinical settings, therefore, targeting cells of the supportive tumor microenvironment is a promising advance to eradicate SCC. Using mouse models of SCC, our previous basic research results uncovered the existence of a direct crosstalk between skin CSC and tumor-associated macrophages (TAM) via Wnt signaling. Interestingly, we observed that Wnt regulated the expression of three CSC receptors, CD99, MFGE8 and Nectin-2, and governed the CSC-TAM crosstalk. Here, I propose to expand this basic research into a translational perspective, to explore the potential of CD99, MFGE8 and Nectin-2 as therapeutic targets for human SCC. There is a major interest in this arena, since the major caveat of targeting Wnt signaling in cancer is the lack of specificity to target CSC, without affecting somatic cells. Moreover, most clinical trials have not been fully efficient to dampen the Wnt response in tumors. Using a comprehensive and integrated approach based on human SCC, cell biology, omics and medical chemistry, along with powerful patient derived xerographs (PDX), my results must likely unearth a role for these immunoreceptors in governing the CSC-TAM crosstalk, and their potential as drug targets for human SSC. This interdisciplinary project will be conducted at the University of Copenhagen (UCPH) in Dr. Perez-Moreno, Dr. Merete Haedersdal, and Dr. Strømgaard groups. Through the CApaCITy project, I will embark in a leading research area with several possibilities to grow into an independent international researcher.