PREDICt

Project Coordinator

Martina Sollini
- Istituto Clinico Humanitas (ICH) IRCCS, Department of Diagnostic Imaging, Rozzano
- Milan - Italy

Project Partners

Markus Luster
- Philipps-University Marburg (UMR), Nuclear Medicine Department
- Marburg - Germany
Ciarrocchi Alessia
- Azienda Unit. Sanitaria Locale di Reggio Emilia-IRCCS (AUSL-IRCCS)
- Reggio Emilia - Italy
Oscar K. Lee
- National Yang-Ming University (NYMU), Stem Cell Research Center
- Taipei - Taiwan

Background and rationale: Radioiodine-refractory (RAI-R) differentiated thyroid cancer (DTC) is a challenging tumor. Several mechanisms have been claimed for RAI-R.
Hypothesis: RAI-R DTC have peculiar assets that underline resistance and differentiate these tumors from RAI-sensitive (RAI-S) ones.
Aims:
- Evaluate the genetic, trascriptomic profiles and the role of cancer stem cells (CSC), epithelial-mesenchymal transition (EMT) and immunity in RAI-R DTC;
- Identify RAI-R DTC biomarkers;
- Develop RAI-R DTC organoids.
Methods: High risk DTC patients (pts) will be enrolled. Pts will be followed as in use in clinical practice. RAI-R pts will be evaluated. An equal number of RAI-S pts, matched for histology, age, sex and tumor stage will be analyzed. Genes, CSC, EMT and immunity profiles as well as biomarkers will be compared in RAI-R and RAI-S. The project will consist of:
- Task 1: Genetic and molecular profiling of RAI-R and RAI-S DTC. Exome sequencing will be performed. Gene expression profile will be investigated. Focus on genes involved in EMT or in CSC biology will be posed to explore their role in RAI-R. CD133+ cells will be isolated and implanted in mice for further analysis. Annexin V and CD133-PE staining will be performed.
- Task 2: Biomarkers profiling of RAI-R and RAI-S DTC. miRNA and proteins will be tested as serum biomarkers. Images will be analyzed (radiomics and/or machine/deep learning approaches) to test their prognostic role.
- Task 3: RAI-R organoids. Tissue samples will be used to develop RAI-R DTC organoids that will be used to evaluate the mechanisms involved in RAI-R and to test drugs that may restore RAI sensitivity.
Expected results and potential impact: Diverse molecular and genetic profiles as well as different biomarkers between RAI-R and RAI-S are expected. The identification of reliable biomarkers will impact on high risk DTC pts management and treatment potentially improving quality of life of pts and healthcare costs.

Our data describe a model according to which the insurgence of aggressive features including radioiodine refractoriness (RAI-R) and distant metastases (DM) in differentiated thyroid cancer (DTC) is associated with a significant inhibition of immunity and immune associated functions.

Our data indicate that inhibition of the TP53 function can be also functionally relevant in the definition of RAI-R/DM phenotype.

The tumor mutation burden was low and no difference were observed suggesting that clinical aggressiveness in DTC is mediated by a high transcriptional plasticity rather than by the acquisition of genetic alterations.

We found that the expression of prostate specific membrane antigen (PSMA) is a predictor of tumor aggressiveness and patient outcome.

Our findings suggested that PSMA expression and [¹⁸F]FDG-PET/CT played a complementary role in DTC risk stratification.

The distinct phenotype known as vessels that encapsulate tumor clusters (VECT), which is associated with metastasis and poor prognosis in some tumors in an EMT-independent manner, was not associated with DTC outcomes (recurrence, RAI-R development, and status at last follow-up), suggesting that in DTC, EMT is a key element for tumor aggressiveness.