Enzo Medico, M.D. Ph.D.
Integrative genomics of cancer progression and resistance to treatment.
Cancer progression involves acquisition by neoplastic cells of several molecular alterations, conferring metastatic ability and resistance to anticancer treatments. Integrative genomics evaluates systematically, in cohorts of tumor samples, multiple layers of molecular information, at the DNA, mRNA and microRNA level. The same analyses are conducted on large series of preclinical models, such as cell lines and patient-derived xenografts (PDXs), to consolidate regulatory network alterations in individual cancers and cancer subtypes, to identify key lesions driving cancer progression and possibly to determine sensitivity to targeted treatments. Extensive validation in the preclinical models allows exploiting the genes as therapeutic targets, and molecular signatures as diagnostic tools for precision medicine.
The Laboratory of Oncogenomics has been focusing on colorectal cancer (CRC) and on the generation and analysis of multi-layer molecular and pharmacological data on large sets of CRC samples, patient-derived xenografts (PDXs) and cell lines. Such analysis was then followed by functional validation of identified candidates and mechanisms of neoplastic progression. The main achievements are here summarized: (i) species-specific genomics of CRC PDXs to distinguish the stromal transcriptome, contributed by murine cells, from the human epithelial cancer transcriptome, with implications in CRC aggressiveness and resistance to treatment (Nature Genetics, 2015); (ii) identification of mixed mRNA/microRNA networks associated to CRC subtypes (Nature Commun., 2015) and of multi-dimensional networks to uncover cancer drivers (Scientific Reports, 2015); (iii) Integrative pharmacogenomic profiling of a large collection of CRC cell lines (n=151), validating molecular subtypes and providing new actionable expression outliers in specific cases (Nature Commun., 2015) (iv) Development of a procedure for high efficiency in vivo transduction of PDXs with lentiviral vectors (Scientific Reports, 2015); (viii) Identification of NEDD8 pathway inhibition as an effective therapeutic option in KRAS- and BRAF-mutant CRC, and in vivo validation of a molecular response predictor (JNCI, manuscript submitted). Sharing the genomic expertise of the Lab with other groups inside and outside the Institute also led to publication of several collaborative works.
Conclusions and Perspectives:
The Laboratory will continue exploiting integrative genomics for better molecular stratification and for highlighting actionable therapeutic targets in CRC and other neoplastic diseases.