Current research areas

Our group is interested in understanding metabolic, translational and epigenetic changes associated to developmental programs and how their aberrant function leads to cancer and other diseases. The current main topics of our lab are:

1) Hedgehog signaling, epigenetic regulators and their targeting in cancer.

Hedgehog signaling is a critical regulator of embryonic development and stem cell fate. Its aberrant activation has been observed in many forms of cancer, including medulloblastoma, basal cell carcinoma, prostate, lung, breast and colon cancers.

We have identified the epigenetic regulators Histone Deacetylases 1 and 2 (HDAC1 and HDAC2) as key targets of Hh signaling. Upon Hh activation HDAC1/2 are upregulated and remove an inhibitory acetyl group from Gli1 and Gli2, thereby activating transcription. As a consequence, HDAC1/2 levels are increased in Hh-dependent tumors and their targeting is a potential avenue to treat Hh dependent tumors. Using in vivo and in vitro approaches, our lab is dissecting the molecular basis of this mechanism and testing the efficacy and specificity of epigenetic drugs targeting Hedgehog signaling in cancer.


2) Metabolic changes, developmental regulators and diseases

Alteration of cellular metabolism is a key feature of both developing tissues and cancer. We have observed that Hh signaling shifts the proliferating cells toward the utilization of aerobic glycolysis. This process is amplified in Hh-dependent tumors and inhibition of this metabolic switch with the pyruvate kinase inhibitor DCA efficiently counteracts the growth of tumor cells. Further studies are ongoing to analyze how nutrient availability affects Hh signaling and other developmental pathways and tumor growth. We are exploring how energy and metabolic detectors interfere with developmental regulators and are evaluating the effect of selective metabolic compounds.


3) Translational regulation in cancer and other diseases

Protein translation is frequently found deregulated in cancer and other diseases. We have identified a small zinc finger protein, named CNBP, as a key translational regulator involved in development and aberrantly activated in Hh dependent tumors. We have found that CNBP is upregulated by Hh signaling and promotes translation of ornithine decarboxylase (ODC), thereby enhancing the biosynthesis of polyamines, small polycathions involved in cell proliferation and viability. Polyamines are elevated in medulloblastoma and targeting ODC or CNBP efficiently counteracts tumor growth. We are using genetic, biochemical and cell biology approaches to study the molecular mechanisms of translational regulation in cancer and genetic diseases. We are also screening and testing novel inhibitors of protein synthesis.