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Molecular fingerprint of pre-tumor lesions of the pancreas discovered

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Molecular fingerprint of pre-tumor lesions of the pancreas discovered

Intraductal Papillary Mucinous Tumors (IPMN) of the pancreas are one of the many neoplasms that affect this organ. Their peculiarity is that they represent a real puzzle for clinicians because it is difficult to classify them as benign or malignant forms. In fact, risk stratification has so far only made use of clinical and radiological factors because a biomarker of malignancy is not available. This creates classification uncertainties, which have repercussions on the choice of whether or not to initiate the patient towards demolitive surgical treatment or continue surveillance. A study just published on Nature Communications by the professor’s research group Giampaolo Tortora, professor of medical oncology at the Catholic University of the Sacred Heart and director of the Comprehensive Cancer Center of the Gemelli Polyclinic, partially fills this knowledge gap. Researchers have in fact identified specific tissue biomarkers, a sort of molecular fingerprint, which allows us to distinguish with certainty benign forms from those with a high degree of malignancy or at high risk of malignant transformation. To arrive at these results, researchers from Università Cattolica – Gemelli examined an incredible amount of data on surgical pieces of patients treated at Gemelli over the last ten years, making use of omics analyzes and in particular sophisticated spatial transcriptomic and proteomic technologies. . Their work thus made it possible to identify lesions on tumor tissue ‘molecular signatures’ which indicate low-grade dysplasia (HOXB3 and ZNF117), those of ‘borderline’ cases (SPDEF) and finally the markers of high-grade dysplasia, i.e. definitely malignant forms (NKX6-2). This work not only provides an important new diagnostic tool to differentiate benign from malignant pre-tumor pancreatic lesions, but also sheds light on the role of the activation of some genes (TNFalpha and MYC) in the progression of IPNMs from a benign form to a malignant (ductal pancreatic adenocarcinoma, or PDAC). The newly published research was supported by a grant from the AIRC Foundation for Cancer Research (“Luigi Bonatti and Anna Maria Bonatti Rocca”), assigned to Dr. Carmine Carboneteam leader of the study and researcher of Fondazione Policlinico Universitario Agostino Gemelli IRCCS. What are IPMNs. Pancreatic intraductal papillary mucinous neoplasms are cystic lesions that develop inside the pancreatic ducts and which contain ‘shoots’ of tissue (papillary projections) lined with mucous epithelium. The frequency of these cysts with uncertain behavior, which are discovered by chance during a CT scan or MRI done for another reason, is increasing and grows with advancing age. A recent meta-analysis from the Mayo Clinic (USA) reveals that IPMNs are discovered by chance in approximately 11% of over 50s undergoing abdominal CT scans. However, certain data on prevalence and incidence are lacking.

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An absolute necessity is therefore to create a Italian register of IPMNs – claims Professor Tortora – because we are certain that their number is widely underestimated”. These tumors arise from the pancreatic ducts and are considered precursors of pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive neoplasm for which limited therapeutic options are available. But with current knowledge it is not possible to predict the course of their natural history and therefore identify with certainty those at greatest risk of malignant transformation. The forms considered to be at high risk (based on the CT scan) undergo surgery immediately, while those at low risk undergo surveillance (i.e. MRI every 6 months).

So far then – explains Professor Tortora – the risk stratification of IPMNs is done only on the basis of clinical characteristics (especially high-risk IPMNs that develop in the main ducts) and radiological (CT scan, MRI), while no criteria were available that took their biology into account. This means that up to 10% of IPMNs considered ‘low risk’ – admits Professor Tortora – escapes correct evaluation and, over time, can give rise to an aggressive tumor”.

The research conducted at the Catholic University and the Gemelli Polyclinic makes an important contribution to the identification of lesions with a high potential for malignant transformation. “And this is an important indication – underlines Professor Tortora – because if it is essential to identify the lesions at high risk of malignant transformation, it is equally crucial to define the characteristics of ‘benignity’, to avoid patients having a useless, very invasive and not risk-free surgery”.

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How to manage a patient with IPMN

Once the diagnosis of IPMN has been made, the patient undergoes an MRI check-up every 6 months to monitor the lesion and subject it to a biopsy if its appearance changes. “Until now we did not have any parameters, beyond the morphological (radiological) ones – recalls Professor Tortora – that could help us to understand in reasonable advance what the evolution of a lesion could be in order to orient the therapeutic process towards a wait-and-see behavior or immediately proceed to demolitive surgery (in fact, there is no ‘reductive’ intervention for the IPMN only)”.

A precision diagnosis

With a patient and meticulous study of Spatial transcriptomics and proteomics carried out on tissue (i.e. on the operating piece) – recalls the doctor Carmine Carbone (team leader of the study and researcher of Fondazione Policlinico Gemelli e corresponding author of the work, together with the first author of the study, Dr Antonio Agostiniresearcher at the Agostino Gemelli IRCCS University Polyclinic Foundation) – we analyzed the cells that make up the IPMNs one by one to study their RNA and corresponding proteins, respecting the cytoarchitecture of the tissue. In this way, it was possible to highlight that the forms with a lower or greater risk of malignant transformation differ in the expression of some genes and proteins; specifically, gene expression NKX6-2, confers an increased risk of malignant differentiation; on the contrary, the expression of genes HOXB3 e ZNF117 indicates a low-grade dysplasia, therefore a benign condition. The next step will consist in the search for a prognostic biomarker of tumor transformation in the blood”. “At the moment – says Professor Tortora – the only tumor marker associated with pancreatic cancer is CA 19-9, but finding it high already indicates the presence of pancreatic adenocarcinoma”.

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The pathways of cancer and therapeutic prospects

The study published on Nature Communications also highlighted that the TNFalfa and the MYC they are the molecular ‘pathways’ through which the transformation of a pre-cancerous lesion into a frankly tumorous one travels. “So in the future – continues Dr. Carbone – we could hypothesize the development of treatments capable of blocking these ‘pathways’ (an anti-MYC is already under study). But there’s more. With theranostics, we could try to conjugate an antibody targeted against NKX6-2 with a radiopharmaceutical to precisely target the tumor cells that express this gene, an indicator of malignancy, by exploiting the ‘good nuclear’.”.

An Italian task force against pancreatic cancer

The news of the creation of one came a few days ago control room for pancreatic tumors, at the Ministry of Health, which aims to encourage the creation of a network of Pancreas Unit Centers, to improve the diagnosis and treatment of pancreatic tumors. The Working Groups, coordinated by the professor Sergio Alfieri (ordinary of General Surgery at the Catholic University of the Sacred Heart, director of the Department of Medical and Surgical Sciences of the Agostino Gemelli IRCCS University Polyclinic Foundation and Scientific Clinical Director of the Isola Tiberina-Gemelli Isola Hospital) bring together the leading pancreatic cancer experts from all over Italy; among these, Professor Giampaolo Tortora, who together with his collaborators signed this important publication on Nature Communications.

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