Dissecting the role of miRNAs and other ncRNAs in the tumor microenvironment.
Studying the involvement of ncRNAs in the development of cancer resistance to therapy, and how ncRNAs can be effectively used to restore drug sensitivity.
Identifying signatures of dysregulated ncRNAs with diagnostic, prognostic and theranostic implications in pediatric tumors.
MicroRNAs (miRNAs) are small molecules of RNA (one of the two types of nucleic acids present in the cells) which are not translated into proteins but regulate the expression of other genes. MiRNAs have been found differentially expressed in almost all types of human cancers versus the normal tissue counterpart and are key players in the development of tumors. MiRNAs belong to a bigger family of RNAs, called non-coding RNAs (ncRNAs) whose expression is also dysregulated in cancer.
My research focuses on investigating the role of miRNAs (and other ncRNAs) in cancer growth and dissemination, and in the development of cancer resistance to therapy, which ultimately represents the main cause of cancer-related deaths.
The goals of my studies are to be able to develop ncRNA-based anti-cancer treatments and provide patients with a new additional weapon against the disease.
Cancer is the most complex genetic disease. It develops within a specific environment of surrounding cells and molecules (called the tumor microenvironment), which are involved in cancer growth, dissemination and development of resistance to treatment.
Dr. Fabbri discovered that miRNAs are secreted by cancer cells in the surrounding tumor microenvironment, within microvesicles (called exosomes). Exosome-contained miRNAs (namely, miR-21 and miR-29a) can be engulfed by the immune cells surrounding cancer cells and they can bind to Toll-like Receptor 8 (TLR8) present in the immune cells. As a consequence, TLR8 is activated and the immune cells release interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), which increase tumor growth and metastatic potential.
This pioneering research showed a completely new mechanism of action for miRNAs (able to bind and activate a receptor in a hormone-like fashion) and identifies a novel molecular link between cancer, inflammation and immunity. The implications of this discovery are geared towards the identification of new drugs able to interfere with this miRNA-mediated cross-talk between cancer cells and the surrounding tumor microenvironment, leading to novel anti-tumor agents.
- A specific cluster of miRNAs (namely, the miR-15a/16-1 cluster) induces apoptosis by targeting BCL2. PNAS 102(39):13944-13949, 2005.
This study identifies the first target gene of miRNAs in human chronic lymphocytic leukemia (CLL). The miR-15a/16-1 cluster is located in the most frequently deleted region in CLL (the 13q region) and this study provides the first evidence that restoring miR-15a/16-1 expression leads to anti-tumoral effect by silencing the anti-apoptotic BCL2 gene.
- Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 12(3):215-229, 2007.
This study is the first to show that another group of ncRNAs (namely, the transcribed ultraconserved regions) is also frequently dys-regulated in cancer and provides the first evidence of a regulatory mechanism of miRNAs on the ultraconserved regions.
- MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. PNAS 104(40):15805-15810, 2007.
This study shows that miRNAs can actually affect gene expression by regulating their epigenetic status. It is the first report showing that a family of miRNAs (namely, the miR-29 family) directly targets two key enzymes of the epigenetic machinery (DNMT 3A and DNMT 3B). This leads to the re-expression of tumor suppressor genes (such as WWOX and FHIT), silenced by promoter hypermethylation in cancer, and to an overall anti-tumoral effect. We subsequently demonstrated that the other key DNMT enzyme (DNMT1) is indirectly targeted by miR-29 family, explaining the profound hypo-methylating effect observed upon miR-29 restoration in cancer cells (Blood 113(25):6411-6418, 2009).
- MiR-15a and miR-16-1 cluster functions in human leukemia. PNAS 105(13):5166-5171, 2008.
This study shows the magnitude of miRNA impact on the genome of cancer cells. It is the first report to show that a specific cluster of miRNAs (namely, the miR-15a/16-1 cluster) affects, directly and indirectly, the expression of about 14% of the genes in the whole human genome, revealing the broad spectrum of effects that miRNAs exert on the human genome.
- Modulation of mismatch repair and genomic stability by miR-155. PNAS 107(15):6982-6987, 2010.
This study provides the first evidence of an involvement of a specific miRNA (miR-155) in cancer-associated genomic instability. MiR-155, frequently up-regulated in several human cancers, directly target mismatched repair genes and increases genomic instability, ultimately leading to a more malignant phenotype. This effect is also exerted by miR-21, which increases drug resistance by targeting MSH2 (PNAS 107(49):21098-21103, 2010).
- Association of a microRNA/TP53 feedback circuitry with the pathogenesis and prognostic factors of B-Chronic Lymphocytic Leukemia. JAMA 305(1):59-67, 2011.
This paper identifies a feedback circuitry, involving the miR-15a/16-1 and the miR-34b/c clusters, the tumor suppressor gene TP53 and tumor marker ZAP70, able to explain the prognostic implications associated with some of the most common chromosomal aberrations (the 13q, 11q and 17p deletion) in human CLL.
- MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. PNAS In press, 2012.
This paper identifies a completely novel mechanism of action for miRNAs. They are secreted by cancer cells and can bind to TLR7 (in mice) and TLR8 (in human) in the surrounding immune cells. By binding to TLRs, cancer exosome-released miR-21 and miR-29a induce NF-kB activation and secretion of IL-6 and TNF-alpha by the immune cells, which ultimately leads to increased cancer proliferation and metastatic potential.