Project Funding Details

Hormonal regulation of carcinogenesis critical impacts the onset of tumors and their progression to malignancy. Keratinocyte Skin Cancers, consisting of Basal Cell Carcinoma (highly proliferative but rarely metastatic) and cutaneous Squamous Cell Carcinoma (cSCC, often metastatic and accounting for 20% of annual skin cancer-associated mortalities) are by far the most common malignant neoplasm in humans. Thyroid hormones (THs) are key endocrine regulators that, from development to adult life, regulate cell-fate determination and differentiation in normal and pathological contexts. Over a century of research has supported a tight correlation between THs and the pathophysiology of cancer. Research from our lab has pioneered the concept that in the cSCC, the intracellular activation of THs, by the activating enzyme Type 2 Deiodinase (D2), fosters the tumor progression and the metastatic conversion. More recently, we observed that the D2/TH axis repress the expression of DNA repair and oxidative genes, thus favoring the accumulation of genomic instability, metastasis, and resistance of epithelial cancers. Since we argued that D2-produced T3 negatively impacts the genomic integrity, leading to chromosomal instability during tumour invasion and metastasis, we hypothesize that inflammation might be a key intermediate in triggering genomic instability. This project includes three Specific Aims: SA1. Reveal early, mid, and late TH-dependent response transcriptomic signatures in ex vivo cSCC tumour cultures. SA2. Decode the TH role in the inflammation-modulated metabolic reprogramming as hallmark in skin cancer. SA3. Test new druggable anti-TH agents as therapeutic candidates to counteract the "inflamma-damaging" effects induced in metastatic cSCC. In SA1, the whole TH-dependent transcriptomic signatures will be investigated by deep RNA sequencing followed by Gene Set Enrichment Analysis (GSEA) of RNA-seq data on a panel of 5 different immortalized patients-derived cSCC cells in a dose-dependent time-course of THs treatment. In SA2, we will assess the extent of TH-induced inflammation and its relevance for the induction of metabolic reprogramming in two sets of experiments: metabolomics and cytokine/chemokine profiling on serum samples (secretome analysis), and in vitro isotope-resolved metabolomic analysis in patient-derived cSCC cells, to assess a molecular characterization of the pathways in which the newly TH-dependent identified metabolites are involved. Finally, in SA3 we will test the efficacy of two new druggable anti-TH agents as biomedical tool for cell-based therapies in skin tumors by in vitro and in vivo characterization experiments. By dissecting the function of D2/TH axis in the temporal regulation of cellular processes, such as inflammation, metabolic reprogramming, and DNA Damage Response, we will reveal novel unexplained mechanisms underlying hormonal control of cancer growth and their therapeutic implications. This project will enable us to identify the TH-induced metabolic fluctuations and networks within epithelial cancer cells that functionally affect cancer cell progression toward metastasis. Furthermore, we will provide proofs-of-concept evidence that the inhibition of D2/TH axis in epithelial cancer cells may pose as a therapeutic tool against metastatic spread of tumors.