Epidermal Growth Factor Receptor (EGFR) is a cell surface protein with tyrosine kinase activity, and a major effector of extracellular signals promoting cell growth and survival, as well as developmental tissue differentiation. EGFR is also considered a proto-oncogene, since its aberrant/constitutive activation is responsible for cancer cell growth and invasive properties; furthermore, its upregulation leads to resistance to targeted therapies in human tumors. Due to its major impact in cell function, EGFR is subject to several regulatory mechanisms, at transcriptional, post-transcriptional, and post-translational levels. Moreover, a range of EGFR-interacting proteins controls EGFR activation, trafficking and intracellular signaling. Moreover, was recently found that specific cell surface co-receptors, as for example Neuropilins, play a major role in EGFR regulation, with potential relevance for cancer therapy. Intriguingly, Neuropilin-1 (Nrp1) has also been found to control the internalization of microRNAs (miRNAs) exchanged via the extracellular space (and circulating plasma), which are thereby translocated into the cytoplasm of Nrp1-expressing cells for the regulation of targeted transcripts. This novel function could represent an important mechanism of EGFR regulation, since multiple players of this signaling pathway are targeted by miRNAs. In sum, our project aims at elucidating novel mechanisms regulating EGFR signaling, via the uptake and internalization of circulating miRNAs.
The possibility to interfere with circulating miRNAs which impact on EGFR pathway activity in cancer cells may represent a powerful tool for the design of innovative therapeutic approaches for cancer patients. The project may also lead to the identification of functional miRNAs that could represent diagnostic markers for human cancer. Based on results from this proposal, a patent might be filed for: i) therapeutic use of circulating miRNAs (through the use technologies selectively targeting the miRNAs complex), and ii) diagnostic/prognostic markers specific for cancer subtypes (based on the presence of membrane Nrp1/2 and specific circulating miRNAs). The advancement of knowledge in cancer biology, guaranteed by this synergy project, would lead to a higher level of comprehension of the mechanisms sustaining cancer malignancy. The overall impact of this project on scientific knowledge is summarized in: i) identification and validation of unique circulating miRNA impacting on EGFR signaling pathways; ii) dissection of the contribution/specificity of membrane Nrp1/2 to miRNA internalization; iii) identification of the biological relevance of cellular internalization of circulating miRNA on tumorigenesis; assessment of the susceptibility of cancer cells to internalized miRNAs; iv) development of in vitro models to evaluate the contribution of circulating miRNAs on the efficacy of targeted therapies directed to EGFR.