Thyroid Cancer

Thyroid cancer (TC) is the most common tumor of the endocrine system. Papillary Thyroid Carcinoma (PTC) is the most common thyroid cancer subtype and it is usually characterized by slow growth rate and rare metastatic spreading, resulting in a favorable prognosis for most patients. In spite of the low-risk profile, nearly 5% of PTCs behave aggressively developing distant metastasis.

In this setting, the lack of biomarkers to discriminate between highly aggressive and indolent tumors at diagnosis, arises the issue of patients’ overtreatment.

We investigate the molecular bases of thyroid cancer by several approaches to provide new instrument to improve management of cancer patients.

Mila Gugnoni, Gloria Manzotti, Benedetta Donati, Francesca Reggiani, Emanuele Vitale, Cristian Ascione, Federica Torricelli, Veronica Manicardi, Elisa Salviato

Transcriptional dependencies in TC: the role of RUNX2

Transcriptional dependency defines the addiction of cancer cells to specific TFs that are on top of the regulatory hierarchy governing the cancer dysregulated program. RUNX2, a mammalian RUNT related TF is recognized in cancer biology for its oncogenic properties and has been linked with tumor progression, metastasization and resistance to anti-cancer therapies. However, still little is known on how this TF works at the molecular level to support cancer progression. Using TC as disease model, we aim to combine functional genomic and next generation sequencing approaches to annotate the genome-wide function of RUNX2. Connecting its transcriptional activity with the biological function of its target genes and with the clinical behavior of TC patients in vivo will serve to explain why TCs are addicted to RUNX2 function and to define potential strategy to target this TF in patients.

Long non-coding RNA in TC

Long non-coding RNAs (lncRNAs) are emerging as relevant molecular determinant in cancer. We are using several approaches to study the contribution of these molecules to cancer progression. Our data indicate that these transcripts contribute to TC aggressiveness in several ways from the control of autophagy and resistance to stress (linc00941) to transcriptional regulation (RAIN).

Development of a genetic signature for the early identification of patients with high-risk papillary thyroid carcinoma

Even if considered indolent lesions, the majority of Papillary Thyroid Carcinoma (PTC) patients undergo radical treatment without a proper risk-based stratification with risk of severe overtreatment. The identification of robust prognostic tool for the early identification of aggressive lesions is mandatory to improve PTC management. Using a genome-wide approach, we identified a gene-based prognostic signature (THYT1), that strongly associated with presence of distant metastasis and reduced survival probability. In virtue of its high specificity and sensitivity, THYT1 candidates to become the first gene-based prognostic tool for risk stratification in PTCs. The aim of our activity in this area is to establish a highly reproducible and easy to access assay to detect this signature in the daily practice and applied this signature on the pre-surgical diagnostic setting.

Spatial Transcriptomic to map ATC evolution

Anaplastic thyroid cancer (ATC) is the most aggressive and lethal form of thyroid cancer. These lesions rarely develops as ex-novo tumors but rather evolves from pre-existing well-differentiated TCs through a de-differentiation process Deepening the knowledge of these mechanisms is necessary for developing targeted therapies and prognostic panels that will provide each patient with the most suitable treatment. To this aim, we are applying a spatially resolved, high-dimensional transcriptomic approach to define and validate the main drivers of ATC evolution.

Moreover, by using a systematic drug repurposing approach based on gene expression we aim at identifying “old drugs” able to re-sensitize ATC to standard therapies. The application of this approach may represent an alternative and efficient strategy to identify ready-to-use new treatments for rare diseases, such as ATC.