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Tumor Cell Biology

ITT Core Research Laboratory
c/o Department of Pathology and Experimental Oncology
Viale GB Morgagni 50
50134 Florence - Italy
Phone: +39 055 4598258
Fax: +39 055 4598900

Principal Investigator: Dr. Barbara Stecca, PhD

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The Unit Tumor Cell Biology has started his research activities in May 2009. Our research aims at understanding how signalling pathways and gene expression programs control normal development, and how disruptions of these processes lead to tumorigenesis and cancer metastasis. We are approaching these questions through the study of the Hedgehog-Gli (Hh-Gli) signalling pathway.

Main Research Themes

The Hh-Gli pathway plays critical roles in development, homeostasis and cancer. Hh ligands bind to the membrane Patched-Smoothened receptor complex and elicit a cascade of cytoplasmic signal-transduction events that lead to the activation of the Gli zinc finger transcription factors.

During embryonic development, Hedgehog pathway is critical for normal patterning of diverse structures, such as the digits of the limb or neuronal types in the spinal cord. Later during embryogenesis Hh-Gli is required for proliferation of neural precursors in dorsal brain regions. Loss of Sonic hedgehog causes cyclopia and ventral forebrain-patterning defects. On the contrary, abnormal Hh-Gli pathway activation can induce tumors, such as basal cell carcinoma, medulloblastoma and rhabdomyosarcoma.

In the last few years numerous studies have highlighted a critical role for continuous Hh-Gli signalling activity in driving the growth of an increasing number of human cancers. Our group has found that the blockade of Hh-Gli pathway inhibits cell proliferation, leads to regression of human melanoma and inhibition of lung metastases in immunocompromised mice. Recent studies point to a requirement for Hedgehog pathway activity in maintenance and self-renewal of stem cells. These findings are relevant to cancer, because of the possible derivation of cancer stem cells, a sub-population within a cancer that is capable of its propagation, from adult tissue stem cells. In agreement with this idea, we recently showed that Gli1 increases the number of brain stem cells in a conditional transgenic mouse model. Interestingly, we found that the tumor suppressor p53 negatively controls Gli1, by inhibiting its self-renewal and proliferation activities. We propose that the imbalance between Gli1 and p53 activities, and ultimately p53 loss, a common event during tumor progression, releases the normally restricted activites of Gli1, leading to an uncontrolled expansion of cancer stem cells and their derived progenitors.

Thus it appears clear that a strict regulation of Hh-Gli signalling is critical not only for normal development but also to maintain homeostasis, to control stem cell behavior and to prevent tumor formation. Also, Gli1 functions as a key integration point, where signals from several pathways converge. Still, the identity of its upstream regulators and downstream effectors is only partially known. Our goal is to understand the mechanisms contributing to the regulation of cell growth, transformation and tumor progression by Hedgehog and, in particular, by Gli1. To achieve this goal, we plan to dissect basic signal mechanisms modulating the activity of Gli1 in stem cells and cancer and to identify downstream targets that mediate Hh-Gli responses. To accomplish this aim we use a number of methodologies, ranging from transgenic mouse models to the use of gain and loss of function assays, including the expression of cDNA, RNA interference and viral-mediated gene transfer and silencing. The systems we use include mouse models, human samples, cultures of human and mouse cell lines, primary cells and stem cell cultures.

Publications

  1. Stecca B. and Ruiz i Altaba A. (2009). A GLI1-p53 inhibitory loop controls neural stem cell and tumor cell numbers. EMBO J. 28: 663-76.
  2. Ruiz i Altaba A., Mas C., Stecca B. (2007). The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biology 17: 438-47.
  3. Stecca B., Mas C., Clement V., Zbinden M., Sanchez P., Correa R., Piguet V., Beermann F., Ruiz i Altaba A. (2007). Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and RAS-MEK/AKT pathways. Proc. Natl. Acad. Sci. USA 104: 5895-900.
  4. Stecca B., Ruiz i Altaba A. (2005). Brain as a paradigm of organ growth: Hedgehog-Gli signaling in neural stem cells and brain tumors. J. Neurobiol. 64: 476-90.
  5. Nguyen V., Chokas A.L., Stecca B., Ruiz i Altaba A. (2005). Cooperative requirement of the Gli proteins in neurogenesis. Development 132: 3267-79.
  6. Stecca B., Mas C., Ruiz i Altaba A. (2005). Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol. Med. 11: 199-203.
  7. Sanchez P., Hernandez A.M., Stecca B., Kahler A.J., DeGueme A.M., Barrett A., Beyna M., Datta M.W., Datta S., Ruiz i Altaba A. (2004). Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl. Acad. Sci. U S A. 101: 12561-66.
  8. Ruiz i Altaba A., Stecca B., Sanchez P. (2004). Hedgehog-Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett. 204: 145-57.
  9. Stecca B., Ruiz i Altaba A. (2002). The therapeutic potential of modulators of the Hedgehog-Gli signaling pathway. J. Biol. 1:9.

Collaborations

  • Centre Medical Universitaire (CMU), University of Geneva, Geneva, Switzerland.
  • Plastic Surgery Unit, Regional Melanoma Referral Center, Ospedale S.M. Annunziata, Firenze, Italy.
  • Department of Pathology and Experimental Oncology, Universita’ degli Studi di Firenze, Italy.

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