Since 2012, Dr Marzi has been working "non-coding Genome" laboratory, headed by Dr. Francesco Nicassio, now coordinator of the Center for Genomic Science at IIT@SEMM in Milan.
With a Master Degree in Pharmaceutical Biotechnology and a PhD in Molecular Medicine, the scientific career of Dr.Marzi has been characterised by a general interest in the role of non-coding RNAs (microRNAs, lncRNAs) and their ability to modify the expression of genes, shaping cell fate (Marzi et al. J Cell Biol 2012). To this purpose, he acquired familiarity with both computational and experimental approaches, exploiting several genome-wide approaches (small RNA-seq, RNA-seq, ATAC-seq, ChIP-seq), novel technologies and bioinformatics to dissect regulatory gene networks involved in cell differentiation, stem cell biology and cancer (Muller, Marzi et al., Front. Bioeng. Biotechnol. 2014; Marzi et al. Clinical Chemistry 2016). Furthermore, Dr. Marzi contributed to establish in the last few years fruitful collaborations with other laboratories, developing additional lines of research including the analysis of the transcriptional programs governing the development and differentiation of the central nervous system.
Contributing more than ten publications in high impact journals and an international patent on "Cancer Biomarkers" and their clinical use (Bianchi et al. EMBO Mol Med 2011), Dr. Marzi developed within the noncoding Genome lab at IIT two mail lines of research (see Project section):
Non-coding elements in epigenetic and transcriptional plasticity
Among the millions of cells constituting a tumor, there are often a few that can survive treatment and cause tumor relapse and metastatic dissemination. Through genetic events, such as mutations, and non-genetic (“epigenetic")mechanisms, these cells adapt to challenging environmental conditions and make the tumor progress. Current therapies, such as chemotherapy, are severely hindered by the difficulty dealing with these “adaptive responses”.
In our lab, we investigate the non-coding elements that contribute, both at RNA level (ncRNAs) and DNA level (“enhancers"), to shaping the "adaptive responses" that allow cancer cells to survive, disseminate and metastasize.
We predict that a targeted therapy based on these regulators should be successful in eradicating cancer cells surviving chemotherapy.
Epigenetic plasticity (i.e., transcriptional heterogeneity) has emerged as a new hallmark of cancer, as it can give cells the ability to adapt to challenging environmental conditions, such as cancer therapy or metastasis formation. At the mechanistic level, adaptation is regulated by the complex interplay between dynamic regulatory elements (such as enhancers) and their target genes, which ultimately determine the cell response. Unfortunately, only a tiny fraction of the hundreds of thousands of regulatory elements in our genome has been characterized.
With this project, we mainly aim to identify enhancer-gene and lncRNA-gene interactions that are functionally relevant for breast cancer adaptative processes.
So far, we have been focusing on triple-negative breast cancer, an aggressive tumor sub-type characterised by extensive heterogeneity and few therapeutic options. We have already developed several experimental models with high epigenetic plasticity and employed cutting-edge genomic approaches (including NET-Cage, single cell ATAC sequencing and Nanopore sequencing) to identify the regulatory elements (~600 lncRNAs and ~1000 enhancers) that are putatively involved in adaptive responses (e.g. response to chemotherapy, cancer stem cells).
We are currently investigating the functional and transcriptional impact of perturbing each of these regions. Our innovative strategy combines CRISPR interference with single cell RNA sequencing by assigning a unique transcribed barcode to each sgRNA. In this way, single-cell RNA-seq profiles can be used to investigate which cell programs are affected by each individual perturbation. With this approach, we want to identify the cis- and -trans regulatory networks that control cancer cells ability to adapt to therapy.
In the long term, our study will allow us to identify diagnostic targets and therapeutic markers and improve the patients' survival rate.
This project is supported by a ROCHE individual grant to Dr. Marzi.
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Citations: 486 (Scopus)
Total Impact Factor: 102.4