Intraductal papillary mucinous neoplasms (IPMN) are one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC), a lethal disease predicted to become the second leading cause of cancer-related deaths in Western societies within a decade. The mechanisms underlying IPMN progression are poorly understood. The goal of IPMN management is to reduce the risk of patient death due to progression to PDAC through primary and secondary prevention (namely, early diagnosis and risk-reducing surgery). High-risk IPMNs (i.e., high-grade or main duct IPMNs, which account for 57-90% of cases) are referred for surgical resection, while low-risk IPMNs (6-46%) undergo periodic follow-up aimed at monitoring the acquisition of morphological features associated with malignancy over time. However, the clinical management of IPMN remains a significant challenge because the distinction between high and low-risk progression is based on imaging and histological criteria that are not unequivocally recognized and do not take into account the underlying biology of lesions that appear similar but are associated with different clinical behaviors. Consequently, patient risk stratification is often inaccurate, leading to suboptimal treatment. Approximately 1-11% of low-risk IPMN patients assigned to clinical follow-up have developed PDAC. Therefore, it is of paramount importance to improve the understanding of the biology and malignant potential of IPMN to improve prognosis and clinical management of affected patients and guide them toward personalized therapeutic approaches. The availability of markers capable of stratifying IPMN based on their risk of progression to PDAC could enhance the current malignancy criteria assessed in clinical settings by more accurately identifying patients who strongly need surgical resection.

**Study Objective** The aim of this study is to identify and validate biomarkers capable of distinguishing between low-risk and high-risk IPMN progression to PDAC. These biomarkers would help more accurately identify IPMN patients who could benefit from therapeutic intervention and/or surgical resection in the future. The study will include patients with IPMN followed at Fondazione Policlinico Gemelli IRCCS Roma, Fondazione G. Pascale IRCCS Naples, Azienda Ospedaliera Universitaria Integrata Verona, and Azienda Ospedaliera Universitaria Integrata Messina.

**AIM1.**

1. **Identification** of genes and biological pathways associated with IPMN malignant transformation. The investigators aim to explore the molecular dynamics of tumor progression, focusing on cellular heterogeneity and phenotypic transitions.
2. **Characterization of the microenvironment** to understand its role in IPMN progression. The investigators will collect archival samples from 240 patients across four centers.
3. **Identification and validation in plasma** of selected patients of differentially expressed markers in indolent IPMN, invasive IPMN, and PDAC.

**AIM2.** The investigators will develop knowledge-based tools for diagnosing and treating IPMN and at-risk populations.

**AIM3.** The investigators will validate the role of key genes in IPMN carcinogenesis using in vitro study models.

Inclusion Criteria:

• Diagnosis of indolent IPMN under monitoring;
• Diagnosis of malignant IPMN or resectable pancreatic adenocarcinoma with associated IPMN (previously untreated); Written informed consent; Male and female patients aged 18 years or older;

Exclusion Criteria:

-Inability to provide written informed consent or to trace patients for the retrospective study.

Patients >18 years old with Pancreatic IPMN. This cohort will consist of IPMN tissues collected via Formalin-Fixed Paraffin-Embedded from patients who have either developed or have never developed pancreatic cancer associated with IPMN.