Functional genomics of cancer
While great progress has been made in recent years toward a better understanding of the molecular basis and in the development of more effective preventive, diagnostic and therapeutic tools, prognosis for many different forms of cancers remains dismal. High-throughput genomic technologies have shed light on the multifaceted lesions, both genetic and epigenetic, that characterize tumor cells and reinforced the notion that only a comprehensive understanding of these lesions would allow a more incisive and ultimately effective cancer treatment. The goal of the laboratory of Functional Genomics of Cancer is to contribute to unravel the genes and mechanisms causative of a selected group of epithelial and hematological cancers, using the most recent genomic and epigenomic technologies, and to rigorously validate the resultsemerging from these analysis. Cancer is a devastating burden for patients and their families. Our ambition is to provide the scientific community with a fully validated set of genes and pathways that could become targets for focused therapeutic strategies.
Research activities (updated 2014)
Our laboratory is currently pursuing the following lines of research:
- Role of histone methylation and demethylation in cancer development
In the nuclei of eukaryotic cells, DNA is packed into chromatin. The basic constituent of chromatin, the nucleosome, is comprised of 147 bp of DNA wound around an octamer of core histone proteins.
Post-translational modifications of the N-terminal tails of these core histone proteins, modulate chromatin configuration, resulting in changes in transcriptional regulation. These epigenetic modifications are controlled by complex enzymatic machinery that, when deregulated, disrupt normal transcriptional programs. Indeed, genomic alterations of MLL, NSD1, CREBBP, WHSC1L1 and WHSC1, all encoding proteins involved in histone modification, have been implicated in several cancer types.
Through genomic analysis and large-scale highthroughput sequencing we have identified genetic lesions affecting histone methylases and demethylases and we are exploring the role of the genes implicated in these genomic rearrangements in the development of multiple myeloma, lung cancer and renal carcinoma.
- RNA metabolism in cancer
The pathways leading to RNA catabolism are poorly characterized, and even less their potential role in cancer. We have identified genetic lesions affecting genes at the crossroad of various RNA metabolism pathways. Ongoing experiments are evaluating their role in dysregulating oncosuppressive and oncogenic mechanisms in cancer cells.
- Receptor tyrosine kinase receptors in the development of Multiple Myeloma
The protein kinase is the most commonly represented Pfam domain encoded by cancer genes. Many carcinogenic tyrosine kinases are receptors, which are often overexpressed and/or mutated in a variety of tumors. Therapeutic agents targeting this class of receptors have proven to be highly effective in the clinical setting. We have conducted a genomic and proteomic survey of primary multiple myeloma samples, a deadly hematological cancer and have identified two overexpressed RTKs. The goal of this project is to elucidate the nature of the signaling mediated by these RTKs in MM, both in vitro and in vivo, with the final goal of identifying more effective drugs against this deadly disease.