Pancreas, the molecular fingerprint of the cysts that announce a tumor has been discovered

A discovery that solves a real puzzle, that of Intraductal Papillary Mucinous Tumors (Ipmn) of the pancreas, one of the many neoplasms that affect this organ, but which represent a problem 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. And this creates classification uncertainties, which have repercussions on the choice of whether or not to send the patient towards destructive surgical treatment or to continue surveillance.

Specific biomarkers identified

The discovery, which comes from 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. As? Researchers have identified specific tissue biomarkers, a sort of molecular fingerprint, which allows us to certainly distinguish benign forms from those with a high degree of malignancy or at high risk of malignant transformation.

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Examination of the data

To arrive at these results, the researchers from Università Cattolica – Gemelli examined an incredible amount of data on surgical specimens of patients treated at Gemelli over the last ten years, making use of omics analyses, and in particular of sophisticated transcriptomic and spatial proteomics. Their work has thus made it possible to identify on tumor tissue the “molecular signatures” that 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 one (ductal pancreatic adenocarcinoma, or PDAC) – explain the researchers -. The study just published was supported by a grant from the AIRC Foundation for Cancer Research (“Luigi Bonatti e Anna Maria Bonatti Rocca“), assigned to Dr.’s project 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 tissue “shoots” (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 by the Mayo Clinic (USA) reveals that IPMNs are discovered by chance in approximately 11% of over 50s undergoing abdominal CT scanning. However, certain data on prevalence and incidence are lacking.

An Italian register

“An absolute necessity is therefore to create an Italian register of IPMNs – claims Tortora – because we are certain that their number is widely underestimated”. These tumors originate from the pancreatic ducts and are considered precursors of pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive neoplasm for which there are limited therapeutic options. 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 – continues Tortora – the risk stratification of IPMNs has been done only on the basis of the clinical characteristics (especially the IPMNs that develop in the main ducts are at high risk) 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” escape 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 Tortora – because if it is fundamental to identify the lesions at high risk of malignant transformation, it is equally crucial to define the characteristics of “benignness”, to avoid patients having a useless, very invasive and not without risks.”

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How patients are managed

But how do you manage a patient with IPMN? Once the diagnosis has been made, he is subjected to an MRI check every 6 months to keep the lesion under control and subject it to a biopsy if its appearance changes. “Up until now we have not had any parameters, beyond the morphological (radiological) ones – recalls Tortora – which could help us 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 undergone demolitive surgery (in fact there is no ‘reductive’ surgery for the IPMN)”.

“With a meticulous spatial transcriptomic and proteomic study carried out on tissue (i.e. on the surgical specimen) – explains Carbone (also author of the work, together with the first author of the study, Dr. Antonio Agostini, researcher at Fondazione Policlinico Universitario Agostino Gemelli IRCCS) – we analyzed the cells that make up 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. In particular, the expression of the NKX6-2 gene confers an increased risk of malignant differentiation; on the contrary, the expression of the HOXB3 and ZNF117 genes 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 – adds Tortora – the only tumor marker associated with pancreatic cancer is CA 19-9, but the fact of finding it high already indicates the presence of pancreatic adenocarcinoma”.

The pathways of cancer and therapeutic prospects

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

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An Italian task force against pancreatic cancer

A few days ago there was news of the creation of a control room for pancreatic tumors, set up at the Ministry of Health, which aims to encourage the creation of a network of Pancreas Unit Centres, to improve the diagnosis and treatment of tumors in question. The Working Groups, coordinated by the professor Sergio Alfieri (full professor 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 experts in pancreatic tumors from all Italy. Among these, Professor Tortora himself, who signed this publication in Nature Communications together with his collaborators.