Translational Oncogenomic Laboratory


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Research

Genome-wide analyses of cancer specimens for the identification of new diagnostic/prognostic biomarkers.
The development of new genome-wide approaches and the completion of the human genome sequencing offer powerful opportunities to increase knowledge and progress in cancer research, and to tailor cancer diagnosis and treatment to individual patients. However, to gather a deeper understanding of the basic mechanisms that control and determine cancer transcriptome, descriptive (phenotypic) oncogenomics must evolve into a more functional genome-wide approach. To this end we need to implement innovative technological approaches to identify new target molecules and define protein/DNA/RNA modifications that (a) alter gene expression control in cancer cell progenitors during transformation and tumor progression, (b) are responsible for cancer cells response to therapy.

For many cancers it occurs that patients with tumors of the same clinicopathological stage may not have the same disease progression, response to clinical treatments, rate of disease recurrence and survival. In these cases a deep molecular characterization could greatly improve treatment choice and potentially improve survival. In the last years microRNAs (miRs) expression profile is emerging among the best markers for diagnosis, staging and treatment of cancer. To paint a molecular portrait of HNSCC, mesothelioma, breast, cholangiocarcinoma, gastric and colon cancers, which are characterized by the need of biomarkers able to stratify patientsí subpopulations and predict clinical outcome, we performed microRNAs expression profiling using the Agilent platform. These genome-wide studies were performed in close collaboration with various surgical departments at IRE. These analyses lead to the identification of groups of microRNAs that are specifically altered in tumor tissues compared to autologous normal and/or adjacent peritumor tissues in each malignancy. Moreover, the expression levels of several microRNAs was correlated to specific clinicopathological features of patients and showed the ability to predict recurrence-free and/or overall survival rates. The combination of data obtained from expression profiling with data from the ongoing mutational/methylation profiles will likely provide new relevant biomarkers to be used in the development of new targeted anticancer therapies.

The research group is historically involved in studies concerning the gain-of-function (GOF) activity of mutant p53 proteins. In particular, two aspects of mp53 GOF are object of our interest:
(a) the transcriptional activity exerted by mp53 through the interaction with additional transcription factors, that leads to the modulation of genes involved in carcinogenesis, (b) the interaction of mp53 with other p53 family members (p63 and p73), that leads to the impairment of the transcriptional activity of these last.

Concerning the transcriptional activity of mutant p53, we are currently involved in studies aimed at evaluating the ability of mutant p53 to modulate microRNAs expression. We indeed demonstrated that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression in NSCLC cells (Donzelli et al., 2011). p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. We observed that mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-Fluorouracyl treatments. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance.
Aside from lung cancer, we are also investigating associations existing between mutant p53 proteins and altered microRNA expression in head/neck squamous cell carcinomas. By sequencing
TP53 gene in HNSCC samples and integration of this information with that of microRNA profiling we could assess that p53 mutations are associated with differential expression of several microRNAs. Many of these altered microRNAs are interestingly associated with patientsí survival rates. Current studies are functionally characterizing the activity of mp53 proteins in the altered expression of these miRNAs.

Relatively to point
(b), we have recently shown that short peptides of 8 to 10 residues (named SIMPs) that resemble the DNA binding domain of p73 are capable to selectively disassemble protein complexes involving mutant p53 and p73. To evaluate the in vivo functional relevance of SIMPs we generated tumor xenografts in BALB/c nude mice using breast and colon cancer cell lines carrying endogenous mutant p53. Intravenous injection of SIMPs alone or in combination with other anticancer agents evidenced the ability of SIMPs to efficiently inhibit tumor growth in vivo. Additional in vivo studies are currently evaluating the possible clinical application of these molecules for human cancer treatment.

Study of transcriptional co-factor YAP. We have originally shown that the transcriptional co-activator YAP interacts with long forms of TA-p73 and TA-p63 but not with wt-p53 and short isoforms of both p73 and p63. Furthermore, p73, YAP and PML proteins form an auto-regulatory feedback loop which becomes pro-apoptotic in response to anticancer DNA damaging agents. Ongoing research is devoted to the further elucidation of the molecular mechanisms underlying the involvement of YAP in transcriptional and functional axis in response to DNA damage.




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