Tumor cell biology
ITT Core Research Laboratory
c/o Department of Pathology and Experimental Oncology
Viale G.B. Morgagni 50, 50134 Firenze
Tel: +39 055 4598258
Fax: +39 055 4598900
e-mail: barbara.stecca@ittumori.it
Principal investigator: Barbara Stecca, PhD
| Team members | |
|---|---|
| Silvia Pandolfi | PhD student |
| Junia Penachioni | Post-doc |
| Maria Cristina Vinci | Post-doc |
Introduction
The Unit "Tumor Cell Biology" started his research activity in May 2009. Our research aims to understand how signaling 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) signaling pathway. Hh-Gli signaling plays an important role in determining proper embryonic patterning and in controlling growth and cellular fate during development. In the adult, Hh-Gli pathway contributes to homeostasis and regeneration of certain tissues. Its aberrant activation drives tumorigenesis in humans and animals. Secreted Hh ligands (Sonic, Indian and Desert) initiate signaling in receiving cells by binding and inactivating the 12-pass transmembrane receptor Patched (Ptch), which relieves its catalytic inhibition on the 7-pass transmembrane protein Smoothened (Smo). Consequently, active Smo triggers an intracellular signaling cascade that ultimately enables activation and inhibits the formation of repressors of the Gli zinc finger transcription factors. Thus, Hh signaling regulates the function of the three Gli proteins and their activation. Among the targets, there are regulators of proliferation and differentiation, survival, self-renewal, angiogenesis and invasiveness (Figure below).
Figure 1 - Schematic representation of the Hh-Gli signaling pathway (see text).
Main research themes
Role of the Hh-Gli signaling in controlling behavior of melanoma stem cells.
In the last few years numerous studies have highlighted a critical role for continuous Hh-Gli signaling activity in driving the growth of an increasing number of human cancers, including melanomas. We have reported that Hh-Gli pathway blockade inhibits melanoma cell proliferation in vitro and leads to regression of melanoma xenografts and lung metastases in immunodeficient mice (b). Recent studies point to a requirement of the Hh-Gli pathway for survival and self-renewal of stem cells. These findings are relevant to cancer, because of the possible derivation of cancer stem cells (CSC), a sub-population within a cancer that is capable of its propagation, from adult tissue stem cells. Although there is no definitive consensus on the phenotype and frequency of CSC in the majority of human tumors, cells with tumor-initiating potential and self-renewal ability have been reported in human melanomas (c). However, the identification of genes that are necessary for the maintenance and self-renewal of melanoma stem cells (MSC) is lacking. We plan to isolate and characterize MSC from patients and investigate the requirement of Hh-Gli signaling for their proliferation and self-renewal in vitro and in vivo, by testing their tumorigenic and metastatic potential. Through these studies, we expect to shed light on melanoma stem cell biology and identify novel mechanisms involved in the maintenance and tumorigenicity of MSC. Moreover, the finding of a role of Hh-Gli pathway in regulating MSC survival might hold important implications for the development of novel therapeutic approaches. This is particularly relevant for melanoma, which is an extremely aggressive cancer with no therapy available to improve patient survival once metastasized.
Modulation of Hh-Gli signaling in stem cells and cancer.
Recent data point towards a context-dependent interplay between Hh-Gli signaling and oncogenic and tumor suppressor inputs that modulate the activity of the three Gli transcription factors (d). In particular, Gli1 functions as a key integration point, where signals from several pathways converge. We and others have shown that oncogenic RAS and AKT1 potentiate Gli1 function, by enhancing its transcriptional activity and nuclear localization, and counteracting its cytoplasmic retention by the negative regulator Suppressor of Fused in different human cancer cells, including melanoma (b). Interestingly, Gli1 is also controlled by the tumor suppressor p53. We recently reported that p53 inhibits Gli1 self-renewing and proliferative activities and that, in turn, Gli1 represses p53, establishing an inhibitory loop. These findings suggest a model for a novel homeostatic mechanism in which p53 controls Gli1 activity. Any imbalance of the Gli1-p53 regulatory loop that favours Gli1, such as inactivation or loss of p53, a common event during tumor progression, releases the normally restricted self-renewing and proliferative activities of Gli1, leading to an uncontrolled expansion of cancer stem cells and their derived progenitors (d). Thus, it is clear that a strict regulation of Hh-Gli signaling is critical not only for normal development but also to maintain homeostasis, to control stem cell behavior and to prevent tumor formation. However, the identity of Hh-Gli regulators is only partially known. Our goal is to understand the mechanisms contributing to the regulation of cell growth, transformation and tumor progression by Hedgehog. To achieve this, 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. We are using a number of methodologies, ranging from transgenic and knock-out mouse models to the use of gain and loss of function assays. The systems that we employ include mouse models, human samples, cultures of mouse and human cell lines, patient-derived primary cells and stem cell cultures
References
- Teglund S, Toftgård R: Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta. 2010; 1805: 181-208.
- Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V, Beermann F, Ruiz i Altaba A: Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA. 2007; 104: 5895-900
- Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B: The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature 1988; 32: 371-4.
- Kinzler KW, Vogelstein B:< The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol 1990; 10: 634-42.
Research Grants
- 2010-2012 Associazione Italiana per la Ricerca sul Cancro, € 166.980
- 2010-2011 Ricerca Regionale in Materia di Salute, anno 2009 € 160.000
- 2010-2012 Ente Cassa di Risparmio di Firenze € 150.000
Main collaborations
With units within ITT
- Plastic Surgery Unit, Regional Melanoma Referral Center, Azienda Sanitaria di Firenze
- Department of Pathology and Experimental Oncology, University of Florence
- Department of Dermatology, University of Florence
With other Italian and foreign units
- Consorzio per il Centro di Biomedicina Molecolare (CBM) and University of Trieste
Publications
- Stecca B, Ruiz i Altaba A: A GLI1-p53 inhibitory loop controls neural stem cell and tumor cell numbers. EMBO J 2009; 28: 663-76.
- Ruiz i Altaba A, Mas C, Stecca B: The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biology 2007; 17: 438-47.
- Stecca B, Ruiz i Altaba A: Brain as a paradigm of organ growth: Hedgehog-Gli signaling in neural stem cells and brain tumors. J Neurobiol 2005; 64: 476-90.
- Nguyen V, Chokas AL, Stecca B, Ruiz i Altaba A: Cooperative requirement of the Gli proteins in neurogenesis. Development 2005; 132: 3267-79.
- Stecca B, Mas C, Ruiz i Altaba A: Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol Med 2005; 11:199-203.
- Sanchez P, Hernandez AM, Stecca B, et al: Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci USA 2004; 101: 12561-66.
- Ruiz i Altaba A, Stecca B, Sanchez P: Hedgehog-Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 2004; 204: 145-57.
- Stecca B, Ruiz i Altaba A: The therapeutic potential of modulators of the Hedgehog-Gli signaling pathway. J. Biol 2002; 1: 9-12.
