Research topics
(1) Characterization of molecular mechanisms driving diffusion and homing of human metastatic colorectal cancer (CRC). (2) Identification of novel molecular markers to be exploited in patients that are not eligible for current targeted approaches.

Background
CRC is the second cause of cancer-related death in the developed world. Despite progress in surgery and introduction of target therapies for advanced CRC, metastatic seeding remains a leading cause of mortality for most patients. (1) Homing of colon cancer cells to secondary tumor sites, typically the liver, is a nonrandom process driven by a crosstalk between tumor cells and components of host tissues. Elucidating such molecular and functional connections will provide tools for an earlier diagnosis and more specific therapy, with consequent improvement of patient care in the next future. (2) Recent data indicate a role for mutated KRAS and BRAF in CRC progression and metastatization, suggesting that deregulation of important cellular pathways can induce genotype and phenotype changes contributing toward cancer progression. Unfortunately, patients harboring a mutation in these genes are not eligible for innovative target therapies.

Achievements
(1) We obtained the following results: (i) by integrating ex vivo combinatorial peptide selection on a panel of patient samples with bioinformatics, genetics and biochemistry, we profiled a large network of protein interactive sites forming an extracellular signature of the hepatic metastasis microenvironment; (ii) within this signature, we discovered a novel class of ligand motifs that selectively bind hepatic metastasis cells; (iii) we described a liver-specific protein as a mimic of such motifs and a potential novel player in the crosstalk between normal liver and hepatic metastasis; (iv) we isolated a receptor for this protein, a so far unknown supramolecular complex that is selectively present on the surfaces of metastatic CRC cells; (v) we tested the feasibility of modular systems in which a metastasis-specific peptide has the function of targeting an active compound to the hepatic metastasis. (2) We recently created an intramural team to combine proteomics, genetics, and bioinformatics with the final goal of finding broadly applicable biomarkers for the management of CRC.

Goals
(1) To elucidate the role of the described molecules in hepatic homing and colonization by circulating CRC cells in vitro (cells), ex vivo (human samples) and in vivo (animal models); to investigate the diagnostic and/or prognostic significance of the these metastasis-specific molecular markers, to support management of CRC patients; to produce prototype targeted tools to selectively address diagnostic and therapeutic compounds to the microenvironment of hepatic metastasis secondary to CRC. (2) To assess whether and how the microenvironment of liver metastases is influenced by genetic alterations in specific oncogenes. By a combined biological-genetic-bioinformatics approach, we will identify peptide/protein signatures selectively associated to metastasis microenvironment with controlled genetic backgrounds. For this purpose, human samples, as well as in vitro or in vivo KRAS/BRAF mutant models of metastatic colorectal cancer will be employed.

Internal collaborations
Unit of Surgical Oncology: correlation of molecular and clinical data; Labs of Oncogenomics and Molecular Genetics: targeted approaches for diagnosis and therapy; Lab of Molecular Pharmacology: tissue collection and animal models; Lab of Vascular Oncology: identification of biomarkers; Lab of Complex Systems: gene and protein signatures, sequencing and phage display data handling/analysis.