By studying thyroid tumorigenesis, we recently identified interleukin 8 (IL8/CXCL8) as a crucial paracrine/autocrine factor that induces the epithelial-to-mesenchymal transition (EMT) and increases stemness features of thyroid cancer (TC) cells. IL8 acts by binding CXCR1 and CXCR2 receptors on TC stem cells (TCSCs), and CXCR2 can also bind CXCL1, another cytokine produced by TC cells. Given the crucial role of the IL8 pathway in TCSCs, we aim to dissect the molecular mechanisms involved in IL8-mediated TC EMT and stemness and to assess the impact of such mechanisms on its tumorigenicity/metastatic phenotype by:
- Isolating TCSCs from various TC cell lines and human samples by exploiting their biological properties (e.g., growth in non adherent conditions). Characterization of stemness will be assessed by analysis of specific stem gene expression signature.
- Determining the distinct role(s) of each component of the IL8/CXCL1 and CXCR1/2 circuit and of downstream stemness related genes (NANOG, ITGA4, CD38, MYCN) in controlling TCSCs tumorigenic features (cell proliferation, self-renewal, invasiveness, tumor initiating ability, chemoresistance).
- Identifying novel IL8 transcriptional targets in TCSCs and testing their functional relevance in TC.
- Identifying novel IL8 mediated alteration in cancer stem cell metabolism.