Oncogenomic Unit

Azienda Ospedaliero-Universitaria Pisana
c/o IFC-CNR
Via Moruzzi 1 - 56124 Pisa
Tel. + 39 050 315 2780
Fax + 39 050 315 3327
e-mail: laura.poliseno@gmail.com

Tumor cell biology - team members Principal investigator: Laura Poliseno, PhD

Team members
Claudia Mattioli PhD, Post-doctoral Fellow
Marianna Vitiello Phd Student
Ilaria Rizzo Graduate Student
Simone Lubrano Undergraduate Student
Elisa Mercoledí Undergraduate Student,
Andrea Tuccoli PhD, Research Assistant,

Main research themes

Melanoma is the most dangerous type of skin cancer, responsible for almost 60% of the deaths. Each year about 160,000 new cases are diagnosed worldwide and about 48,000 melanoma-related deaths are reported. Furthermore, despite efforts to improve self-awareness and prevention and contrary to the more common breast, lung, colorectal and prostate cancer, melanoma incidence keeps increasing: the 4 to 6% annual increase shown by melanoma is the highest among all cancer types and will cause a doubling of the number of diagnosed patients every 10-20 years [1].

Figure 1: Pseudogenes function as competitive endogenous RNAs (ceRNAs). Representative example of a tumor suppressor gene (i.e. PTEN) and its highly homologous pseudogene (i.e. PTENP1) that share microRNA recognition elements (MREs) in their 3’UTR. The pseudogene, acting as a decoy, sequesters microRNA molecules away from the coding mRNA, contributing to its upregulation and hence opposing to tumorigenesis. Image taken from: http://www.focushms.com/features/old-dog-reveals-new-tricks/


Melanoma is historically considered one of the most therapeutically challenging malignancies. Localized melanoma can be treated by surgical resection with a cure rate of 80%, but metastatic melanoma (MM) patients still have a median overall survival of only 6-9 months and an extremely poor 5-year survival rate (less than 5%) [2]. After decades of stagnation, anti-MM therapy has been recently boosted by newly-developed immunologic and oncogene-targeted drugs, which have shown better results than conventional chemotherapy, in terms of both response rate and progression-free/overall survival [3-5]. However, currently available therapeutic regimens are all plagued by the phenomena of intrinsic and acquired resistance: not all patients respond to treatment and those who initially respond will invariably show signs of progressive disease within few months [6]. The chemoresistance of melanoma cells is at least partially due to their high degree of heterogeneity and plasticity. Current therapeutic approaches fail to completely eradicate the tumor because they are not able to kill the full spectrum of malignant cells and allow the expansion of insensitive/resistant sub-populations [7].
 microRNAs are short 18-25nt single stranded RNA molecules that act as negative post-transcriptional regulators of gene expression by binding to partially complementary sites (microRNA recognition elements, MREs) and causing a decrease in target RNA stability and translation [8]. microRNAs are drivers of human cancer (the loss of tumor suppressive microRNAs can enhance the expression of target oncogenes, while the increased expression of oncogenic microRNAs can repress target tumor suppressor genes) and they are widely used as biomarkers of diagnosis, prognosis and drug resistance [9, 10].
The discovery of a biological function for different classes of long non-coding RNAs, such as large intergenic non-coding RNAs, natural antisense transcripts and pseudogenes, has contributed to reconcile the apparent paradox that the vast majority (>90%) of the human genome is translated, while only 1-2% of it encodes for proteins. Long non-coding RNAs affect the expression of protein-coding genes acting at the epigenetic, transcriptional or post-transcriptional level. In particular, we have contributed to discover that pseudogenes act as competitive endogenous RNAs (ceRNAs) that bind to microRNA molecules and sequester them away from other targets, opposing to microRNA-mediated post-transcriptional regulation [11] (Figure 1). Long non-coding RNAs are deregulated in human cancer, where they can exert oncogenic and oncosuppressive activities [12, 13].
The main research themes of the Oncogenomics Unit, which started its research activities in June 2012, are:
1. to improve the management of metastatic melanoma patients by identifying microRNAs associated with resistance to conventional and targeted therapeutic approaches and by evaluating their ability to predict its onset and monitor its course.
2. to achieve a deeper understanding of the molecular bases underlying the biological properties of melanoma cells by annotating the non-coding part of their transcriptome. Both short (microRNAs) and the different classes of long non-coding RNAs will be identified and their involvement in melanoma genesis, progression and chemoresistance will be studied.


References

  1. Garbe, C. and U. Leiter, Melanoma epidemiology and trends. Clin Dermatol, 2009. 27(1): p. 3-9.

  2. Rubin, K.M. and D.P. Lawrence, Your patient with melanoma: staging, prognosis, and treatment. Oncology (Williston Park), 2009. 23(8 Suppl): p. 13-21.

  3. Flaherty, K.T., et al., Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med, 2010. 363(9): p. 809-19.

  4. Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010. 363(8): p. 711-23.

  5. Hauschild, A., et al., Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet, 2012.

  6. Ko, J.M. and D.E. Fisher, A new era: melanoma genetics and therapeutics. J Pathol, 2011.

  7. La Porta, C.A., Mechanism of drug sensitivity and resistance in melanoma. Curr Cancer Drug Targets, 2009. 9(3): p. 391-7.

  8. Huntzinger, E. and E. Izaurralde, Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet, 2011. 12(2): p. 99-110.

  9. Lujambio, A. and S.W. Lowe, The microcosmos of cancer. Nature, 2012. 482(7385): p. 347-55.

  10. Cortez, M.A., et al., MicroRNAs in body fluids--the mix of hormones and biomarkers. Nat Rev Clin Oncol, 2011. 8(8): p. 467-77.

  11. Poliseno, L., et al., A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature, 2010. 465(7301): p. 1033-8.

  12. Gutschner, T. and S. Diederichs, The Hallmarks of Cancer: A long non-coding RNA point of view. RNA Biol, 2012. 9(6).

  13. Kalyana-Sundaram, S., et al., Expressed pseudogenes in the transcriptional landscape of human cancers. Cell, 2012. 149(7): p. 1622-34.



Main Collaboration

  • Other CRL-ITT Units
  • Istituto di Fisiologia Clinica, CNR, Pisa,
  • Laboratory of Integrative System Medicine, IIT/IFC-CNR, Pisa
  • Dipartimento Oncologico, Azienda Ospedaliero Universitaria Pisana
  • Department of Dermatology, IMCG, New York University, New York, USA
  • Division of Biostatistics, New York University, New York, USA
  • Center for Computational Science, University of Miami, Miami, USA
  • Department of Medicine and Pathology, BIDMC-Harvard medical School, Boston, USA

Research grants

  • ITT Start-up funding 2012-2015

Publications

  1. Poliseno L., Tuccoli A., Mariani L., Evangelista M., Citti L., Woods K., Mercatanti A., Hammond S. and Rainaldi G. MicroRNAs modulate the angiogenic properties of HUVECs. Blood. 2006 Nov 1; 108(9):3068-71.

  2. Poliseno L., Pitto L., Simili M., Mariani L., Riccardi L., Ciucci A., Rizzo M., Evangelista M., Mercatanti A.,Pandolfi P.P. and Rainaldi G. The Proto-oncogene LRF is under post-transcriptional control of miR-20a:implications for senescence. PLosOne 2008 Jul 2; 3(7):e2542.

  3. Maeda T., Ito K., Merghoub T., Poliseno L., Hobbs R.M., Wang G., Dong L., Maeda M., Dore L.C., Zelent A., Luzzatto L., Teruya-Feldstein J., Weiss M.J. and Pandolfi P.P. LRF is an essential downstream target ofGATA1 in erythroid development and regulates BIM-dependent apoptosis. Dev Cell. 2009 Oct; 17(4):527-40.

  4. Poliseno L., Salmena L., Riccardi L., Fornari A., Sup Song M., Hobbs R.M., Sportoletti P., Varmeh S., Egia A., Fedele G., Rameh L., Loda M. and Pandolfi P.P. Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal. 2010 Apr 13;3(117):ra29.

  5. Poliseno L., Salmena L., Zhang J., Carver B., Haveman W.J., and Pandolfi P.P. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010 Jun 24;465(7301):1033-8.

  6. Rose A.E., Poliseno L., Wang J., Clark M., Pearlman A., Wang G., Vega Y Saenz de Miera E.C.,Medicherla R., Christos P.J., Shapiro R.L., Pavlick A.C., Darvishian F., Zavadil J., Polsky D., Hernando E., Ostrer H. and Osman I. Integrative genomics identifies molecular alterations that challenge the linear model ofmelanoma progression. Cancer Res. 2011 Feb 22.

  7. Penna E., Orso F., Cimino D., Tenaglia E., Lembo A., Quaglino E., Poliseno L., Haimovic A., Osella-Abate S., De Pittą C., Pinatel E., Stadler M.B., Provero P., Bernengo M.G., Osman I. and Taverna D. microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C. EMBO J. 2011 Apr 5.

  8. Salmena L., Poliseno L., Tay Y., Kats L. and Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011 Aug 5;146(3):353-8.

  9. Poliseno L., Haimovic A., Christos P.J., Vega Y Saenz de Miera E.C., Shapiro R., Pavlick A., Berman R.S., Darvishian F. and Osman I. Deletion of PTENP1 pseudogene in human melanoma. J Invest Dermatol. 2011 Dec;131(12):2497-500.

  10. Huynh C., Poliseno L., Segura M.F., Medicherla R., Haimovic A., Menendez S., Shang S., Pavlick A., Shao Y., Darvishian F., Boylan J.F., Osman I. and Hernando E. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma cells. PLoS One. 2011;6(9):e25264.

  11. Tay Y., Kats L., Salmena L., Weiss D., Tan S.M., Ala U., Karreth F., Poliseno L., Provero P., Di Cunto F., Lieberman J., Rigoutsos I. and Pandolfi P.P. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 2011 Oct 14;147(2):344-57.

  12. Poliseno L., Haimovic A., Segura M.F., Hanniford D., Christos P.J., Darvishian F., Wang J., Shapiro R.L., Pavlick A.C., Berman R.S., Hernando E., Zavadil J. and Osman I. Histology specific microRNA alterations in melanoma. J Invest Dermatol. 2012 Jul;132(7):1860-8.

  13. Poliseno L. Pseudogenes: newly discovered players in human cancer. Sci Signal. 2012 Sep 18;5(242):re5. PMID: 22990117.

  14. Song S.J., Poliseno L., Song M.S., Ala U., Webster K., Ng C., Beringer G., Brikbak N.J., Yuan X., Cantley L.C., Richardson A.L. and Pandolfi P.P. MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling. Cell. 2013 Jul 2. doi:pii: S0092-8674(13)00765-4. 10.1016/j.cell.2013.06.026. [Epub ahead of print]