Main results

 

Colorectal cancer. Molecular determinants of metastatic potential.

1.Colorectal cancer (CRC) with microsatellite instability (MSI) and mismatch repair defetcs have a reduced metastatic potential as compared with microsatellite-stable (MSS) CRC with chromosomal instability

2. The microsatellite unstable CRC are a heterogenous set of tumors. The more the genetic damage of the microsatellite mutator pathway, the lower the chance of metastasis at diagnosis. The presence of genetic damage in the secondary mutator hMSH3 enhances the mutator phenotype, and is itself associated to a reduced metastatic potential

3. Microsatellite unstable CRC have a higher amount of infiltrating CD3+ lymphocytes (ILs) than MSS CRC. The presence of high density CD3+ ILs is associated to a lower rate of distant organ metachronous metastasis. However, in MSS CRC the effective immunosurveillance is restricted to stage II, as in stage III even cancers with high density CD3+ ILs develop metachronous metastases.   

4. Twist1 mRNA is expressed in CRC but not in normal colonic mucosa, together with Snail mRNA, indicting the activation of EMT mediators in CRC. MSI and MSS differently express putative Twist1 proto-ocogene. In MSI CRC, not expressing the protein, Twist1 harbor frameshift mutations in the 3’UTR. In MSS CRC, the rate of expression of Twist1 correlates with ymph node spread. In CRC cells, hypoxia induces the nuclear translocation of putative Twist1.

 

Pancreatic cancer. Expression of CX3CR1 and of its ligand fractlkine was detected in pancreatic cancer and in its precursor lesions (PanIN). The expression of CX3CR1 increased in PanIN together with the degree of dysplasia from PanIN1 to PanIN3, indicating that chemokine receptors are produced early during pancreatic carcinogenesis, and are likely involved in progression and expansion of the neoplastic lesion ultimately culminating in pancreatic cancer. No correlation was found with Kras mutation or with MSI, a phentotype rarely encountered in these tumors.

Main objectives and research lines

 

CRC is a heterogeneous disease, comprising sporadic, familial, and hereditary cases, with different molecular pathogenesis. The main determinant of patient prognosis is the development of distant organ metastasis, which likey reflects the interplay of several pathways acting along the natural history of the disease. It is recognized that MSI CRC have a better outcome than their counterpart with chromosomal instability (CIN), yet other emerging features which can explain for the different metastatic potential of CRC have not been studied as to the MSI signature. This is the case of e the magnitude of the host immune response. So far, evidence exists that MSI CRC are marked by a higher density of ILs, the high density of which is in turn associated with a better prognosis. However, the contribution of MSI cancers to the survival advantage associated with high density ILs in CRC has not been sistematically assessed. In addition to the genetic background and to the (elicited) amount of immune response, morphological and molecular phenotypes of the CRC cells likely are crucial to the development and expansion of distant organ metastasis. These are the epidermal-to-mesenchimal transition (EMT) process, and the mainentenence of cancer stem-cell attributes. EMT collectively defines phenotype changes affecting cell-migration to distant sites, where stem-cell properties are again required for epithelial re-differentiation and clonal expansion. The lab is now focused on characterizing the above mentioned potential determinats of metastatic CRC stratified by MS-status. A specific project will explore the overlap of EMT and stem-cell features as a potential marker of metastatic disease and possibly target of therapeutic intervention.

As an ideal in-depth examination of the transition from efficient immunosurveillance to immunoescape associated with high density of CD3+ ILs, we plan to study the asset of ILs subpopulations (including Treg) and tumor associated macrophages, in CRC of patients with high density CD3+ Ils who experienced disease progression.

 

Pancreatic diseases.

Acute pancreatitis. Explore the role of PTX3 levels in the serum of patients with acute pancreatitis as an early indicator of local inflammation and as a potential marker of severe pancreatitis

Pancreatic cancer. Molecular epidemiology of MSI cancers: prevalence of MSI phenotype in pancreatic tumors. Chemokines expression in pancreatic adenocarcinoma as a tool to explore the tumor microenvironment as a source of signalling promoting tumor progression in the context of an organ disease.

 

Genotypes of inflammation-related genes and human diseases.

HFE mutations and pancreatic disease (in collaboration with Prof. Silvia Fargion; IRCCS Ospedale Maggiore di Milano)

TIR8 SNPs and inflammatory bowel disease (in collaboration with Dr. Cecilia Garlanda, Dept. of Immunology, and Dr. Silvio Danese, Dept. of Gastroenterology, IRCCS ICH)