Ricerc@Sapienza

The innovation of the proposed study is to transfer the use of TEPs circRNAs signatures to the field of NENs. This type of liquid biopsy has been already used in other kinds of solid tumors, in which is able to detect the presence of the neoplasm and in many cases to identify the origin of the primary tumor. One of the main advantages of liquid biopsy is the easy execution (it requires only a blood withdrawal), which make possible to obtain information also in patients with poor clinical conditions (which could contraindicate the execution of a classical biopsy) or in case of poorly accessible neoplastic sites. Moreover, NENs are known to be heterogeneous neoplasms, and a single classical biopsy could be not representative of all lesions, while liquid biopsy better reflects all tumor localizations.
In recent year, it has been demonstrated the role of platelets in systemic and local responses to tumor growth and diffusion. These cells can acquire tumor-associated biomolecules, a process noted as "education". The main characteristics of TEPs is the ability to ingest circulating RNA, including circRNA which is a stable form of RNA. Isolation and sequencing of TEPs-derived RNA will allow to characterize cancer signatures, which can be compared with publicly available datasets. Through the comparison between patients affected by localized and metastatic NETs, tumor transcriptome evaluation could allow the discover of new pathway potentially involved in NET metastatization, which could be used as therapeutic target in these patients.
The identification of specific mutations or overexpressed signaling pathways could, in the future, guide treatment strategies. For example, the overexpression of mTOR (mammalian target of rapamycin) could substantiate therapy with everolimus.
Further studies could be proposed to confirm these preliminary results in a large and multicentric series of NEN patients and also to compare liquid biopsy at baseline and after 3 months of treatment (SSA or surgery). This would allow to monitor therapy and potentially early detect tumor relapse or progression. In case of radical surgical excision, TEPs analysis could confirm the remission of the disease, precociously identifying the cases of minimal residual disease (not detectable by radiological or functional imaging). In case of systemic medical therapy (SSA), the analysis of circRNA from TEPs could promptly evaluate changing in the gene profile expressed by neoplastic cells. The comparison between baseline and post treatment RNA sequencing could identify possible mechanisms linked to therapy resistance, guiding treatment decision.
In conclusion, the results of this study could help identifying processes underling NETs aggressive behavior and provide prognostic information. In particular, the circRNA sequencing may highlight new molecular mechanisms of NETs progression and metastatization. This new knowledge could guide the choice of a tailored targeted therapy through the identification of overexpressed signaling pathways in tumor cells and potentially lead to the development of new treatments.
Main references:
1. Best M G et al. RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. Cancer Cell. 2015 Nov 9;28(5):666-676.
2. Labelle M et al. Direct Signaling Between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis. Cancer Cell. 2011 Nov 15;20(5):576-90.
3. Nilsson RJ, et al. Blood platelets contain tumor-derived RNA biomarkers. Blood. 2011 Sep 29;118(13):3680-3.
4. Poulet G. Liquid Biopsy: General Concepts. Acta Cytol. 2019;63(6):449-455. doi: 10.1159/000499337. Epub 2019 May 15.