Translational Research and Therapeutic Targets in Pancreatic Cancer

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The Marseille Cancer Research Center celebrates its 50th anniversary ! -

The Iovanna / Dusetti team is part of the Translate-it department

Our team focuses on the molecular aspects of PDAC development and progression to improve the currently available therapeutic approaches.

Approximately 450,000 people worldwide die every year due to the PDAC, making it the most lethal cancer. Despite all the efforts made in research over the last few decades, its prognosis has not significantly improved, with a variable survival time after diagnosis ranging from 2 to 3 months to more than 5 years (only in 5% of cases). It is one of the most lethal cancers, primarily due to an often-late diagnosis, limited therapeutic options, the aggressive nature of the cancer, and resistance to chemotherapy, as well as the observed heterogeneity among patients. This heterogeneity can occur at multiple stages of tumor evolution, from the initial genetic mutations that gave rise to the tumor, its interaction with the microenvironment, and resulting from selection pressure and clonal expansion. Our team focuses on the molecular aspects of PDAC development and progression to improve the currently available therapeutic approaches.

Our team has centered its attention on three main areas:

  1. Signaling and metabolism by targeting NUPR1 for PDAC treatment (Juan Iovanna and Patricia Santofimia-Castaño)
  2. Role of the Intra-tumoral Microenvironment in Carcinogenesis by studying the angiogenesis and the microenvironment in PDAC (Roselyne Tournaire), the adhesive Networks and Invasion (Frederic Andre and Veronique Rigot) and finally
  3. Translational research by the development of Personalized Treatments for PDAC (Nelson Dusetti and Juan Iovanna); Utilizing Aberrant Glycosylation Processes as Prognostic Factors and Therapeutic Targets (Eric Mas), studying the role of Post-Translational Modifications (PTMs) in PDAC Biology (Philippe Soubeyran) and Targeting Resistant Phenotypes of PDAC (Nicolas Frauhoffer).


  • Pancreatic Cancer Heterogeneity 
  • Molecular Targets
  • Predictive Medicine
  • Transcriptomic Signatures
  • Aberrant Glycosylation


1. Signalization and Metabolism in PDAC

NUPR1, an intrinsically disordered nuclear protein (IDP), plays a crucial role in PDAC as well as other cancers. Its genetic inactivation leads to complete arrest of tumor development and progression. Developing inhibitors for NUPR1 is complex due to the dynamic structural characteristics of IDPs. Our strategy involved multidisciplinary approaches, resulting in the discovery of ZZW-115, a potent anticancer compound in vitro and in vivo. The use of ZZW-115 showed dose-dependent tumor regression in xenografted mice without apparent side effects. Cellular analysis revealed induction of cell death through necroptosis, apoptosis, and ferroptosis as a consequence of mitochondrial catastrophe. Ongoing research focuses on the mechanism of action of ZZW-115, the molecular partners of NUPR1, its synergy with DNA-damaging agents, and regulatory preclinical studies. The compound ZZW-115 has been protected by a patent, and a startup (PanCa Therapeutics) has been created to advance it towards clinical trials.

2. Role of Intra-tumoral Microenvironment in PDAC Carcinogenesis
Angiogenesis, Microenvironment, and PDAC

Investigation of endothelial-to-mesenchymal transition (EndMT) in PDAC. Tie receptors, particularly Tie1, play a role in blood vessel maturation. Inactivation of the Tie1 receptor induces EndMT in endothelial cells, contributing to the accumulation of fibroblasts in the tumor microenvironment. TNF-alpha inhibits Tie1 expression, promoting EndMT and consequently favoring the development of the tumor stroma. Our objectives include studying the mechanisms of EndMT and evaluating the impact of the microenvironment on EndMT.

Study of the role of cadherin expression in invadopodia formation during the invasion-metastasis cascade. The composition of cadherins fluctuates during the invasion-metastasis cascade. We investigated the relationship between cadherin expression profiles and the aggressiveness of PDAC. Our objectives include identifying a signature of PDAC aggressiveness and determining the impact of cadherins on cancer cell invasion.

3. Translational Research
Development of Personalized Treatments for PDAC

The intra-tumoral heterogeneity of PDAC poses challenges. We have developed a series of tools necessary for the development of personalized treatments, including a biobank of human tumors, xenografts, primary cell cultures, and organoids. We studied their sensitivity to drugs and conducted a multiomic study of these models. Bioinformatic analysis correlating sensitivity with various omics characteristics, using AI tools, allowed us to identify molecular signatures predicting tumor aggressiveness and drug sensitivity, leading to patent filings and the creation of a startup (PredictingMed). We have validated their effectiveness in a series of retrospective studies, and our ongoing research involves the clinical validation of these signatures in prospective cohorts.

Targeting PDAC Resistant Phenotypes

Pancreatic ductal adenocarcinoma (PDAC) faces a substantial challenge with a major limitation in the effectiveness of current chemotherapies such as mFOLFIRINOX and gemcitabine-based treatment regimens. Clinically, this translates into high recurrence rates and chemoresistance affecting approximately 70% of PDAC patients. This project addresses the urgent need to improve treatment responses by studying and characterizing resistant phenotypes of PDAC. Using a multi-layered bioinformatics approach, our research aims to decode intra-tumoral heterogeneity, reveal resistant phenotypes, and design personalized therapies to overcome existing limitations. To achieve this, we have access to patient cohorts at different stages of progression, including metastases, patient samples before and after treatment, extensive single-cell RNA sequencing data, among others. By unraveling the interaction between tumor heterogeneity and drug response, the project strives to enhance treatment efficacy and identify new therapeutic targets, thereby offering hope for better clinical outcomes in PDAC patients.

Associated person (s)
Role of Post-Translational Modifications (PTMs) by the Ubiquitin Family in PDAC Biology

Development of tools to study post-translational modifications (PTMs) by three ubiquitin-type proteins in cell lines. We will identify alterations associated with anticancer treatment and resistance. We will utilize our PDX biobank to study ubiquitination, neddylation, and sumoylation profiles of tumors from each patient. We will focus on potential specific signatures associated with treatment response and aggressiveness.

Use of Aberrant Glycosylation Processes as Prognostic Factors and Therapeutic Targets

Investigation of the role of aberrant glycosylation in PDAC. Our objective is to identify signatures of glycans and glyco-genes correlated with patient characteristics. We are studying the functions of glyco-genes in various processes associated with the progression of PDAC. We use in vitro and in vivo tests to study the implications and potential therapeutic targets.