European School of Molecular Medicine (SEMM), Milan, Italy
Universita’ degli Studi , Facolta’ di Farmacia, Milan, Italy
Liceo Scientifico “P.L. Nervi”, Morbegno (SO), Italy
11/2012-present Post-doctoral position in Dr. Nicassio’s laboratory , IIT, CGS@SEMM, Milan, Italy
08/2013-10/2013 Visiting Scientist in Dr. Ventura’s laboratory, MSKCC, NewYork, US
09/2010-10/2012 Post-doctoral position in the Lymphoma Genomics group, under the supervision of Dr. Bertoni, IOR, Bellinzona, CH
10/2008-08/2010 Post-doctoral position in the group of Prof. PG Pelicci , IEO, Milan,Italy
07/2004-09/2008 Ph.D. Student in the group of Prof. PG Pelicci , IEO, Milan,Italy
Non-coding RNAs in triple negative breast cancer: new perspectives in neoadjuvant chemotherapy
LAY PUBLIC SUMMARY
Characterised by a very negative prognosis, TNBC (triple negative breast cancer) is the most aggressive breast cancer subtype. Due to the lack of targeted therapy, TNBC patients (about 15% of all breast cancer cases) must usually undergo standard chemotherapy with about half of them displaying resistance to it and developing metastasis. Identifying new targets that can be used in the treatment of TNBC is therefore crucial. To this aim, we are investigating the role of non-coding RNAs. These are RNA molecules without protein-coding potential, of which 2 main types exist: short (microRNAs, 20-22bp) and long RNAs (lncRNAs, >200nt). Despite being a recent discovery, these molecules have been significantly implicated in cancer and depicted as having a considerable diagnostic and therapeutic potential. What are the most promising non-coding RNAs ? And how do they serve their functions?
Standard care therapy is reported as failing in 50% of TNBC cases. This failure does not appear to be associated with distinctive genetic features, but rather with the acquisition of an inducible and reversible transcriptional phenotype that enables tumor cells to enter a drug-tolerant state. Due to the transient nature of this response and the intrinsic heterogeneity of cancer, the molecular determinants of such adaptive transcriptional response have so far proven extremely challenging to be identified and characterized.
To overcome these limitations, we set up a cellular model reproducing TNBC cancer cells chemo-adaptation both in vitroand in vivo and investigated transcriptional evolution through the combination of genomics, cellular barcoding and single cell analysis. A number of non-coding RNAs stood out in our analysis and provided new leads in the investigation of the flexible and dynamic control of gene expression that occurs during the adaptive response. We are investigating the role played by these non-coding RNAs in the evolution of breast cancer and, in particular, during the response to treatment.
By using various approaches (i.e. CRISPR/cas9 based genome editing, shRNA, siRNAs, overexpression) in ourin vitro and in vivo models, we plan to manipulate non-coding RNAs levels ad hocwhile administering chemotherapeutic drugs and hence evaluate the outcome in terms of cancer phenotypes, tumor growth and metastatic spread. In addition, we plan to investigate the mechanisms of action of the most promising non-coding RNAs using both biochemical (i.e. RAP, ChiRP) and imaging (DNA/RNA FISH) approaches.
Our results will shed light on the mechanisms of chemo-adaptation in TNBC, pinpointing lncRNAs as new diagnostic molecules and/or potential candidates in combinatorial therapies.
In the recent past, we focused our attention on microRNAs that are involved in the regulation of mammary stem cells in both the physiological (stem cells of the mammary gland - MaSC) and the pathological context (stem cells of breast cancer - CSC). We found that miR-34 family members are absent in stem cells (both MaSCs and CSCs) and have a pro-differentiating role in luminal compartment. In TNBC, miR-34 forced expression significantly reduces the Cancer Stem Cell component and tumor growth, indicating miR-34 as a promising target in future therapies for TNBC (Bonetti et al., Oncogene 2018). In order to assess if miR-34 can be used as a therapeutic tool, we delivered it directly to tumors using a biocompatible system. We loaded miR-34 molecules onto silica nanoparticles and observed that the efficient delivery of active miR-34 both to cells and to mice harboring tumors, lead to a significant reduction in tumor growth (Panebianco et al., Nanomedicine: Nanotechnology, Biology, and Medicine, 2019).
Identification of lncRNA chemoresistance signature in AML
In collaboration with the European Institute of Oncology (IEO), we are working on a project aimed at identifying the molecular determinants involved in the way Acute Myeloid Leukemia (AML) patients respond to standard chemotherapy.
In particular, we aim at identifying long non-coding RNAs in patients that are resistant to standard chemotherapy and at correlating these data with mutational profiles from the same patients. In addition, we want to investigate the role of lncRNAs as biomarkers for early diagnosis of refractoriness and explore their possible therapeutic applications in AML.
2013 Patent application, International Patent Application No.PCT/EP2013/063313 “Method of treating B-cell malignant cancers and T-cell malignant cancers using thienotriazolodiazepine compounds”
First Author: 5 Last Author: 1
Citations: 714 (Scopus)