ONGOING RESEARCH PROJECTS

microRNA expression profile of lymph node metastases: new therapeutic options to defeat lung cancer mortality.

Funding agency: AIRC (https://www.airc.it/ricercatori/i-nostri-ricercatori/fabrizio-bianchi).

microRNA expression analysis in lymph nodal lung cancer metastases can uncover reliable biomarkers for predicting neoadjuvant chemotherapy (NCT) response and novel therapeutics for chemoresistant disease. We are therefore investigating the transcriptional and immunological signatures modulated by miRNA with the aim to identify both intrinsic and extrinsic (exosome- and immune response- mediated) mechanisms, which are relevant to NCT response. Our findings will contribute to unveil how lung cancer become resistant to therapy and how to revert it toward new therapeutics for therapy resistant disease.

Related publications: Cuttano, R., Colangelo, T., Guarize, J., Dama, E., Cocomazzi, M. P., Mazzarelli, F., Melocchi, V., Palumbo, O., Marino, E., Belloni, E., Montani, F., Vecchi, M., Barberis, M., Graziano, P., Pasquier, A., Sanz-Ortega, J., Montuenga, L. M., Carbonelli, C., Spaggiari, L., & Bianchi, F. (2022). miRNome profiling of lung cancer metastases revealed a key role for miRNA-PD-L1 axis in the modulation of chemotherapy response. Journal of hematology & oncology, 15(1), 178. https://doi.org/10.1186/s13045-022-01394-1

Cuttano, R., Afanga, M. K., & Bianchi, F. (2022). MicroRNAs and Drug Resistance in Non-Small Cell Lung Cancer: Where Are We Now and Where Are We Going. Cancers, 14(23), 5731. https://doi.org/10.3390/cancers14235731

Improving lung cancer early detection by developing circulating micro-RNA Biomarkers.

Funding agency: The Italian Ministry of Health (MoH)

The origin of extracellular miRNAs circulating in the blood is still unclear. Extracellular miRNA in body fluids were recently shown to be valuable for developing cancer biomarkers either for early diagnosis and prognostication of lung cancer. Our interest is to explore their origin and how they transfer molecular information among different cell types composing the tumor milieu. The understanding of how tumor cells crosstalk each other and with immune/stromal cells in the tumor microenvironment will unveil mechanisms relevant for tumor onset and progression thus exploitable as novel targets for next-generation drugs.

Related publications: Dama, E., Colangelo, T., Fina, E., Cremonesi, M., Kallikourdis, M., Veronesi, G., & Bianchi, F. (2021). Biomarkers and Lung Cancer Early Detection: State of the Art. Cancers, 13(15), 3919. https://doi.org/10.3390/cancers13153919

Identification of molecular mechanisms which drive tumor cell plasticity and aggressiveness in human non-small cell lung cancer.

Funding agency: The Italian Ministry of Health (MoH)

Tumor cell plasticity (TCP) is a conubium of processes which lead to re-activation of developmental programs correlating with epithelial-to-mesenchymal transition, and ultimately leading to acquisition of stem cell properties and transdifferentiation potential. Till date, little is known about the molecular mechanisms governing TCP in lung adenocarcinoma (LUAD), i.e. the most frequent lung cancer subtype. We recently identified prognostic 7-miRNAs/10-mRNAs signatures which accurately identified aggressive LUAD among patients with early-stage disease (Stage I). Furthermore, we showed that such tumors show TCP features i.e. mesenchymal and stem-cell traits, high-metastatic potential. We are now investigating how TCP is regulated by investigating the transcriptome and immunophenotype of aggressive LUAD in bulk tumor samples and at a single-cell level to explore the mechanisms triggering and governing TCP in lung adenocarcinoma. Our results will possibly suggest novel therapeutic approaches for the management of aggressive LUADunresponsive to actual treatment protocols.

Related publications: Melocchi, V., Dama, E., Mazzarelli, F., Cuttano, R., Colangelo, T., Di Candia, L., Lugli, E., Veronesi, G., Pelosi, G., Ferretti, G. M., Taurchini, M., Graziano, P., & Bianchi, F. (2021). Aggressive early-stage lung adenocarcinoma is characterized by epithelial cell plasticity with acquirement of stem-like traits and immune evasion phenotype. Oncogene, 40(31), 4980–4991. https://doi.org/10.1038/s41388-021-01909-z

TOGGLER: Theranostics fOr aGGressive Lung cancER

Funding agency: The Italian Ministry of Health (MoH)  (project number: PNRR-POC-2023-12377322).

TOGGLER will develop and validate innovative theranostics biomarkers to defeat lung cancer mortality. The project is focused on exploiting patented lung cancer biomarkers based on miRNA expression profile in order to identify aggressive lung cancer and develop innovative antibodies therapeutics.

Dissecting the role of micro-RNAs in regulating the PD-L1 immune checkpoint in lung cancer

Funding agency: AIRC

This project aims to launch an in-depth investigation of miRNA-mediated molecular mechanisms that regulate PD-L1 expression in NSCLC by identifying miRNAs as well as the target genes and pathways they utilise to regulate PD-L1, and the effects of miRNA-mediated PD-L1 regulation on immunotherapy response in NSCLC. Expected outcomes include the identification of an ex-vivo miRNA signature linked to PD-L1 expression, a comprehensive understanding of miRNA roles in PD-L1 regulation, and novel insights into the complex regulation of PD-L1 in lung cancer. Consequently, this study will significantly enhance the understanding of PD-L1 regulation, and facilitate the discovery of reliable biomarkers for predicting immunotherapy response in cancer patients.