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meeting day with UMR 1068 researchers (CRCM) april 7th, 2020 -

Pancreatic cancer

Approximately 350,000 people worldwide die every year due to pancreatic ductal adenocarcinoma (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). One of the principal problems facing this disease is the heterogeneity observed among patients regarding symptoms, clinical evolution, predisposition to early metastasis, and sensitivity to treatments. Heterogeneity can arise at multiple stages of tumor evolution, from the first genetic mutations that gave origin to the tumor, its interaction with the microenvironment and as a result of selection pressure and clonal expansion. Nevertheless, two clinical subtypes of PDAC have been characterized: basal, with the worst prognosis, and classical. Less than 10% of PDAC patients respond to gemcitabine. This percentage increases three times with FOLFIRINOX, a protocol that combines four different drugs (5-FU, leucovorin, irinotecan, and oxaliplatin). Hence, more than 70% of patients do not respond to the current therapies and even worse, failure of the first line chemotherapy leads to an acceleration of tumor growth conducive to a resistant and metastatic tumor.

Our main projects

identifying personalized treatments against panceatic cancer by investigating the molecular heterogeneity of this disease Nelson Dusetti
studying proteins with tumor suppressive activity Alice Carrier
analyzing the metabolic changes occurring in transformed pancreatic cells Sophie Vasseur
screening novel antitumoral compounds synthesized by us and studying their mechanism of action Juan Iovanna
studying the role of the over-expressed stress proteins in pancreatic cancer cells Juan Iovanna
dissecting the molecular dialogue established between the stroma components and the transformed pancreatic cancer cells Richard Tomasini
analyzing the mechanism of the endothelial-to-mesenchymal transition that occurs in pancreatic cancer Roselyne Tournaire
developing  all necessary tools for studying all known post translational modifications in pancreatic cancer cells Philippe Soubeyran
studying the molecular mechanisms involved in the formation of aberrant glycoconjugates and their clinical impacts

To these ends, we have developed several sophisticated molecular, cellular and animal tolls such as vectors of expression (plasmids, retrovirus, letivirus, etc), complex co-culture systems mimicking the tumor microenvironment, some transgenic, KO, KI and immunodeficient animal models of pancreatic cancer, a platform for middle throughput screening of protein-protein interaction based on an original yeast two hybrid system, a platform for high throughput screening of inhibitor of protein-protein interaction based on the BRET approach and a cell culture platform on ISO9001 standard.

Our laboratory is about 40 people, including scientists, oncologists, gastroenterologists, surgeons, pathologists, informaticians, several engineers and technicians and post doc and PhD students.

Cell Stress teams
Energetic metabolism and oxidative stress

Carcinogenesis and tumor resistance to therapies are supported by strong metabolic modifications, which can be based on stressful conditions such as nutrient, oxidative or inflammatory stress. The hypothesis of my group is that mitochondria, involved in energetic metabolism and oxidative stress, are central in these processes.

The mitochondrial metabolism remains poorly explored in pancreatic cancer despite the central role of these organelles in cell bioenergetics and apoptosis. In that context, our project aims at exploring the impact of mitochondrial alterations in pancreatic cancer (PDAC) development and resistance to therapy.

Our first objective is to decipher mitochondrial features in PDAC tumors, to correlate them with tumor growth and therapeutic resistance, and to develop preclinical assays targeting mitochondria. This approach will contribute to the development of novel targeted cancer therapies and prevention of patient relapses.

Our second aim is to explore how nutritional interventions (physical activity and dietary components) can prevent mitochondrial alterations supporting tumor growth and therapeutic resistance.

Our third objective is to contribute to identify preventable risk factors for PDAC. Some are already well described: obesity, cigarette smoke and alcohol consumption. Epidemiological studies point to specific dietary factors included in Western-type diet (red and processed meat and sweetened beverages) and sedentary lifestyle as major risk factors for PDAC, but experimental studies are still missing to prove the causality.

 

Objectives 2 and 3 are conducted as part of the National Network NACRe (Réseau National Alimentation Cancer Recherche)

Development of personalized treatments for patients with pancreatic adenocarcinoma

Pancreatic cancers evolve according to the combined effect of mutations, selection of resistant cells and clonal expansion. As a result of these phenomena, pancreatic cancer presents a huge intra and inter-tumor heterogeneity directly linked to the terrible prognosis of this cancer. Despite being well documented, the heterogeneity of pancreatic tumors remains poorly addressed. The strategies of study have until now been little effective and biased because of the difficulties encountered with the biological material used for the studies. Among these difficulties, two seem to us the most important:

1-The great stromal content variation in pancreatic tumors (between 15 and 85%), but even more, within different regions in the same tumor. Most studies did not account for this variation and considered the tumor to be a homogeneous mixture of tumor cells and stroma.

2-Up to now the studies were performed only on surgical biopsies because they alone allowed obtaining sufficient amount of material. However, this leads to a selective inclusion of patients because only 15 to 20% of them are eligible for surgery and represent only the less advanced tumors.

In this situation, it is very difficult to characterize tumor heterogeneity at molecular level.

Which is the best strategy to study pancreatic cancer heterogeneity creating efficient tools useful in translational medicine?

In the last years we have developed different strategies to circumvent these difficulties developing tools to personalize existing as well as to identify new and more effective treatments.

1-We have established a tumor biobank based on the in vivo xenograft model. This method allows us to efficiently obtain a homogeneous and almost unlimited amount of cancerous epithelial cells. The stromal cells represent in this model only 10 to 15% and are distributed homogeneously. From these xenografts we have also succeeded in deriving primary cell cultures useful for in vitro studies.

2-Even if the xenograft model is absolutely necessary, it requires between 6 months to more than one year to be established. This lapse of time is incompatible with clinical practice because the life expectancy of patients with pancreatic cancer is very short. To get around this problem we are also working on organoids culture. With this model, cells from tumor samples can be maintained in three-dimensional culture reconstituting the tumor organization. This biobank can be frozen and thawed providing an unlimited source of these micro tumors useful in different types of clinical and/or preclinical studies. One of the greatest interests of this bio bank is the study of tumor sensitivity to known drugs and/or to evaluate new anticancer molecules. Organoids comes from different tumor and represent the huge diversity observed in patients. Thanks to these strategies, all patients with pancreatic adenocarcinoma can be included in our studies, 1 metastatic or locally advanced patients for whom we obtain very small tumor samples by ultrasound and fine needle aspiration. (EUS-FNA) and 2-surgical biopsies from operated patients. A consortium was created for the collection and study of tumor samples with clinicians, gastroenterologists, oncologists and surgeons from the Nord Hospital, La Timone Hospital and the Institute Paoli Calmettes of Marseille as well as biologists and bioinformaticians from the Cancer Research Center of Marseille.

How to approach the study of pancreatic cancers personalization in an efficient manner?

Pancreatic cancer is a systematically fatal disease. The chemotherapy used to treat pancreatic adenocarcinoma is indicated according to the general state of the patients and the stage of their disease progression, but not according to the tumor biology. At a time when personalized medicine seems to be best choice in the treatment of most cancers, it becomes urgent to adapt the treatment to the different subtypes of pancreatic adenocarcinoma and their sensitivity to available drugs. It is in this clinical and biological context that we try to answer the following question: would it be possible to predict the clinical outcome and chemo-sensitivity of pancreatic tumors on the basis of their molecular characteristics? We have developed studies based on the “omic” and high-throughput techniques applied to the biobanks described above that conducts to a functional test based on transcriptomic studies and time-lapse video microscopy, which can be used to determine in just a few weeks the sensitivity of tumors to existing chemotherapies or the potential usefulness of new drugs. Thanks to this we have identified several molecular signatures predicting tumor aggressiveness and sensitivity to different chemotherapeutic drugs. Molecular signatures bring us a new view of tumors beyond histopathological types, grade, and classical stage parameters. They have the attraction of novelty over conventional approaches and can help us tailor treatments to the types of cancer cells that constitute the tumor. They allow extremely precise and sensitive biological tests that can be done on tumors through the detection of a reduced number of biological molecules.

We think that detailed knowledge on the molecular mechanisms underlying pancreatic tumors could allow predicting the clinical course and chemo-sensitivity of this disease. To test this hypothesis, we have developed omic studies and high throughput techniques that led us to the identification of molecular signatures. These signatures allow the realization of highly accurate and sensitive biological tests that can be done on tumors through the detection of a reduced number of biological molecules. Molecular signatures bring us a new view of tumors beyond histopathological types, grade, and classical stage parameters. They have the appeal of novelty over conventional approaches and can help us tailor treatments to the types of cancer cells that make up the tumor.

Associated person (s)

The protein Nupr1/p8 :
In the past we have shown that expression of this gene is necessary for tumor development. Recently, we were able to assign a major role in the regulation of epithelial-to-mesenchymal transition (EMT).

In particular, we demonstrated that expression of Nupr1/p8 is involved in a novel mechanism of cell death called entosis or cellular cannibalism. We have partially dissected the molecular mechanism of this new function of Nupr1/p8 and explored the involved pathways.

Finally, we demonstrated that expression of Nupr1/p8 is essential for the cellular response to nutrient deprivation or hypoxia (metabolic stress), the mechanism involved is dependent of the NFkB alternative (RelB), but not of the classical NFkB pathway (p65). We are currently fully characterizing this very original mechanism.

 

The PAP protein :
We have demonstrated that the interaction of PAP with its receptor activates, on one hand, the Jak-STAT3-SOCS3 and, on the other hand, inhibits the activation of NFkB. These two pathways appear to be involved in the anti-inflammatory effect of PAP.

Because PAP is a secretory protein and we demonstrated the existence of a specific receptor, the PAP-receptor could be a new target for treating certain inflammatory diseases. We are characterizing and trying to clone it.

 

VMP1 protein :
We demonstrated that expression of VMP1 is “necessary and sufficient” to trigger autophagy. Overexpression of VMP1 induces vacuole formation while the use of a siRNA against VMP1 prevents the recruitment of LC3 and vacuole formation induced by nutrient deprivation or rapamycin treatment.

Then, we developed a transgenic mouse in which overexpression of VMP1 was induced in the pancreas and validated our in vitro studies.

 

Development of new small anticancer compounds :
In collaboration with a team of chemists from the CNRS we are interested in developing new compounds with antitumor activity in pancreatic cancer. Chemists have synthesized hundreds of novel compounds and we have systematically screened their activity in vitro and in vivo.

Among these molecules, we identified two compounds, structurally related, whose activity is higher than that of gemcitabine in vitro as well as in vivo. Our work is currently focusing on optimizing the structure of these molecules and actively researching on their mechanism of action.

Associated person (s)
Regulation of Signaling Pathways

Post-translational modifications and therapeutic escape:
Characterized by a 5 years survival rate of less than 5% the pancreatic cancer (pancreatic adenocarcinoma) remains one of the cancers with the worst outcome. This situation is notably due to the exceptional resistance of pancreatic tumors to conventional anticancer therapies. We think that we have to use original approaches to discover new fighting tools.

Ubiquitination is a post-translational modification process known for several tenths of years. However, this is only these last years that the great potential of ubiquitination to regulate cellular functions has been revealed. We think, and some data confirm it, that defects in ubiquitination play an important role in tumor development and resistance to chemo and radiotherapies.

We are trying to identify the proteins which ubiquitination is modified when pancreatic cancer cells undergo anti-cancer treatments. Then we are studying all candidate proteins by evaluating their importance, and the importance of their ubiquitination, regarding the resistance of pancreatic cancer cells.

Then we try to depict the molecular mechanisms responsible for the changing in ubiquitination of these candidate proteins.This should enable us to develop molecules capable to inhibit these modifications in vitro and importantly in vivo.

Our goal will be then to test these molecules upon the resistance of pancreatic cancer cells.

Microenvironment and Pancreatic Tumorigenesis

Pancreatic ductal adenocarcinoma is characterized by the presence of non-tumor cells constituting the intra-tumoral microenvironment or stroma. Composed by fibroblasts, immune, lymphatic/endothelial and nerve cells, this stroma can represent up to 90 % of tumor mass. Since over 10 years, our group evaluates the implication of intra-tumoral microenvironment in development and evolution of pancreatic cancer, through the role of inter-cellular dialogue, nervous and immune systems. More specifically, our present studies intend to demonstrate how inter-cellular dialogue impact on 1/ capacities and outcome of stroma (particularly cancer associated fibroblasts, CAFs) (Z. Hussain, PhD) and 2/ tumor cells and PDAC chemo-resistance (J. Nigri, PhD). Those two projects should permit to establish an inter-cellular dialogue-based cartography, mediated by extra-cellular vesicles, between stromal compartment and tumor cells. The use of human samples, efficient PDA mouse models combined with omics analyses as Single cell RNA-Seq and Mass spectrometry, as well as a large panel of in vitro approaches, permit to confirm our hypothesis while producing data necessary to the development of transverse and clinical projects.

In parallel, we evaluate 1/ the impact of CAFs/Macrophages connection on their respective activities/abilities and consequent influences on the development of pancreatic cancer as well as their chemo-resistance to conventional therapies (T. Bertran, Post-doctorant), 2/ the potential of PAP/REG3A as a predictive biomarker of PDA patients to be eligible to surgery (ERC-PoC) and 3/ the impact of nervous system in the development and evolution of pancreatic cancer (S. Tubiana, Ingeneer, PAIR Pancreas).

Angiogenesis, Microenvironment and Cancer

Stromal cells provide a microenvironment which is essential for tumoral growth, invasion and metastasis. Fibroblasts are essential components of this microenvironment. Activated fibroblasts (also called myofibroblasts or CAFs for Cancer-Associated Fibroblasts) are localized in close proximity to cancer cells. They are able to modify the phenotype of epithelial cells either by direct cell-cell contact, or through soluble factors, or by modifying the extracellular matrix. The interaction between myofibroblasts and cancer cells is essential for tumor growth and for the formation of metastasis, and the presence of such cells is associated with a poor clinical prognosis. 

Endothelial-mesenchymal transition (EMT) is a process by which endothelial cells disaggregate; endothelial cells change shape and migrate to invade surrounding tissues. EMT is characterized by the loss of endothelial cell markers and the acquisition of mesenchymal cell markers: this process has been reported o occur during embryonic development and in cases of fibrosis.

Mesenchymal cells derived from endothelial cells behave like fibroblasts in damaged tissues.

We are interested in the receptors involved in angiogenesis and more specifically in Tie family receptors, Tie1 and Tie2, which are involved in blood vessel maturation.

We have recently demonsrated, first that the absence of Tie1 in endothelial cells leads to EMT, and second, that EMT occurs in human pancreatic tumors, including in humans. EMT thus contributes to generate the pool of fibroblasts associated with cancer. These data suggest that therapeutic strategies targeting EMT could offer new perspectives for the treatment of pancreatic cancer. Our aims are to analyze the mechanisms involved in EMT and determine the impact of tumor microenvironment on EMT.

Nos objectifs sont d’étudier les mécanismes impliqués au cours de l’EndMT et de déterminer l’impact du microenvironnement présent dans les tumeurs sur la transition endothélio-mésenchymateuse.

Impact of Hypoxic and Metabolic Stress on Pancreatic Tumor Progression

Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumors with an overall five-year survival rate of only 3–5%. Its aggressive biology and resistance to conventional and targeted therapeutic agents lead to a typical clinical presentation of incurable disease once diagnosed. Presence of a prominent non-tumoral cell compartment within the tumor (a main characteristic of PDAC) is directly impacting on patient clinical outcomes.

In PDAC, cancer cells are “isolated” by a fortress of stromal cells, composed of very few blood vessels, which distorts the normal parenchymal architecture of pancreas and limits the oxygen and nutrient diffusion in the tissue. This severe hypoxic environment at the site of the tumor provides a strong selective pressure able to regulate tumor cell growth and to favor survival of the most aggressive malignant cells.

Another hallmark of PDAC is cachexia, defined as an unintend weight loss of 10% or more of the stable weight over a period of 6 months, and associated with loss of fat and muscle tissue. Pancreatic cancer-patients with cachexia often have an elevated resting energy expenditure (REE), a higher rate of more progressed tumor stages and have significantly reduced survival. Hence, this tumor must harbor metabolic pathways which are probably tied in a complex inter-organ dialogue during its development and illustrate this cancer as a real metabolic disease.

One of the major consequences of intra-tumoral hypoxia, combined with oncogene signaling, is the cell metabolic switch occurring in order to meet the requirements of tumor proliferation under low oxygen and low nutrient supply because of lack of vasculature. Since decades it has been accepted that tumor cells display fundamental changes in pathways of energy metabolism and nutrient uptake, and that alterations in cellular metabolism contribute to malignant phenotype. Cancer cells differ from healthy cells due to a plethora of molecular changes which are mechanistically linked to metabolic reprogramming. Metabolic signature of each type of tumor is then strongly associated to oncogenic mutations occurring in the tumor associated cells.

Our project is based on the concept that pancreatic cancer cells are probably metabolically flexible.

However, molecular changes leading to metabolic adaptations of pancreatic cancer cells remain unclear. We propose innovative strategies to abolish PDAC progression, based on the concept that targeting molecules belonging to a specific « PDAC Metabolic Signature » can be a new relevant therapeutic option to treat PDAC.

Based on the metabolic transcriptomic signature of PDAC, we propose strategies targeting molecules mainly involved in lipid, amino-acid and glucose metabolic pathways, 3 essential metabolic processes for energy production and biosynthesis during tumor growth.

Combined therapies to avoid resistance to a single anti-metabolic drug is challenging but appears to be a good strategy to counteract the tumor cell metabolism plasticity and pancreatic tumor progression.

Use of aberrant glycosylation processes as pronostic factors and therapeutic targets

Pancreatic adenocarcinoma (PDAC) is a devastating disease progressing asymptomatically until death within months after diagnosis. The predisposition to metastasize is very important in the development of PDAC and implicates complex molecular mechanisms. In particular, aberrant glycosylation of glycosphingolipids and glycoproteins (glycoconjugates) expressed in tumor cells has been involved as one of essential mechanisms in malignant transformation, cell adhesion and metastatic spread. Although it was shown that expression modifications of glycosyltransferases and glycosidases (glyco-enzymes) play a key role in the formation of aberrant glycoconjugates, little information is available on the regulation of mechanisms that produce altered glycan structures during pancreatic carcinogenesis and their clinical impacts.

Therefore, the first objective of the project is to identify signatures of aberrant glycans and signatures of genes involved in the formation of these aberrant glycans (glycogenes) by means transcriptomic data from pancreatic tumors, correlated with biological and clinical data of patients. These signatures will be used to classify and predict patients outcomes in terms of tumoral progression and metastatic spread. In the context of precision medicine, the identification of these patients through these signatures should allow the establishment of appropriate therapeutic protocols for better care.

 

Moreover, these glycogenes will be new targets that could be used in diagnosis, prognosis and therapies. Therefore, the second objective of the project is to study the role of these glycogenes in the various neoplastic processes of PDAC such as tumor proliferation, aggressiveness, metastasis formation, resistance to chemotherapeutic treatments, etc. Their functions and implications in these processes will be analysed by invalidation techniques (si/shRNA, Crispr/Cas9) or gene overexpression, combined with various in vitro and in vivo functional tests. The oncogenic signaling pathways dysregulated in pancreatic carcinogenesis and involved in glyco-enzymes and aberrant glycoconjugate expressions will also be investigate. Thus, it will be possible to identify and characterize the key-points involved in the modifications of metabolic pathways of aberrant glycoconjugates as potential therapeutic targets to treat pancreatic cancer.

The low survival rates associated with pancreatic ductal adenocarcinoma (PDAC) is due to a diagnosis on the later stage of the disease when local invasion and metastasis to other organs are already developed. PDAC metastasis induces a recurrence and decreases the survival rates of the patients. Therefore, it is essential to characterize new molecular signatures of PDAC aggressiveness to classify patients not only to predict clinical outcomes but also to propose an anti-invasive treatment.

 

During the invasion–metastasis cascade, tumoral cells gradually detach from the primary tumor, and proteolytically degrade the basement membrane and the surrounding extracellular matrix. Cadherin-a type of cell-cell adhesion molecules- composition, fluctuates during this process. According to this, a decrease in the expression of some cadherins (cadherin-1, -10,…) is associated with a increase of some other cadherins (cadherin-2, -3, -17,…) during PDAC progression.

During invasion, tumor cells must be able to degrade and remodel the extracellular matrix. One way in which cells accomplish this task is through invadopodia  which are dynamic protrusions of the plasma membrane found in cancer cells. Invadopodia are able to degrade extracellular matrix through localized accumulation and secretion of membrane-bound and soluble lytic enzymes, mainly metalloproteases. Our recent work suggest that cadherin expression drives invadopodia formation.

 

The aim of this study is to decipher the relationship between cadherin expression profile and the PDAC aggressiveness and poor prognosis. This aim is subdivided in two tasks.

 

1/ We try to identify a signature of PDAC aggressiveness by profiling the cadherin expression in the tumors. In this approach we combine the analysis of cadherin mRNA and protein expression in PDAC samples from patients and in vitro invasion assays. This molecular signature may stratify patients with PDAC and may predict the outcome of the patients.

 

2/ Another objective of our project is to determine whether physical and/or functional interactions between cadherins can regulate cancer cell invasion. To do this, we combine biochemical, imaging and some functional assays (cell migration, cell adhesion,…). We will decipher the impact of each cadherin in PDAC aggressiveness. Moreover, targeting these proteins in pancreatic cancer may be a good anti-invasive and anti-metastatic therapy.

Metabolism of pancreatic cancer (Leader of the group : Vasseur Sophie)

Our group is focused on the understanding of how pancreatic adenocarcinoma (PDAC) rewires metabolic pathways to satisfy the needs of tumor cells in terms of biomass, energy, co-factors for their survival, proliferation in the primary site, and ultimately for their dissemination to distant sites.

Due to a dense micro-environment, PDAC is a poorly vascularized tumor. This poor perfusion at the site of the tumor limits the oxygen (hypoxia) and nutrient diffusion in the tissue and provides a strong selective pressure that favors survival of the most aggressive malignant cells. Based on the transcriptomic signature of PDAC established at both pre-neoplastic and adenocarcinoma stages of PDAC, we established the metabolic profile of PDAC at intermediate and late stages of the disease and revealed that the metabolic reprogramming of tumor cells dynamically evolves with the progression of the disease towards the aggressive stages: we have shown that PDAC develops a metabolic flexibility, acquired thanks to a global reprogramming of amino-acids, lipids and carbohydrates metabolic pathways. Hence PDAC is among the solid tumors subjected to massive metabolic changes which make metabolic targeting of this cancer a promising therapeutic option. We observed that depending on the tumor stage, the oxygen and nutrient microenvironment availabilities, pancreatic cancer cells rewire several particular metabolic pathways which in combination enable them to tolerate stringent microenvironmental conditions specific to PDAC (F. Guillaumond et al. Proc Natl Acad Sci U S A 2013; F. Guillaumond et al. Proc Natl Acad Sci U S A 2015, O. Olivares et al. Nature communications 2017) (Figure 1).

Beyond this « in situ » metabolic adaptation, once PDAC cells have metastasized in distant organs, they must adapt to the new tissue environment to meet their metabolic needs that are required for their expansion to metastatic sites. As more than 80% of patients with PDAC are not eligible for surgery because the tumor itself is not resectable, we are currently searching for metabolic targets to limit pancreatic tumor cells aggressiveness and metastasis formation.

To develop our projects, we integrate bio-informatic analysis into our studies, combined with computational modelling approaches, metabolic tracing, and metabolomics in order to get a dynamic view of the deregulated metabolic pathways in PDAC and its associated metastasis. Thanks to collaborations with clinicians, our studies benefit from a robust clinical validation of our data, necessary to identify relevant key pro-tumorigenic and metastatic metabolic pathways which could serve as new therapeutic opportunities for hosts of this metastatic disease.

Targeting of pro-metastatic metabolic pathways (leader of the project : Vasseur Sophie)

As the microenvironment of metastatic sites (liver, lung, etc…) differs from the PDAC microenvironment with regards to their cellular/matrix components and their available nutrients, several questions arise: To which extent does the metabolic phenotype of primary PDAC cells differ from that of the metastatic cells? How does the microenvironment dictate the metabolic rewiring of tumor cells at primary and distant sites? Along with acquisition of aggressive markers, is the metabolic flexibility acquired by PDAC cells a key event for them to go through the several cellular transition processes needed to metastasize at distant sites? (Figure 2). Using spontaneous metastatic PDAC GEMM, we recently identified a distinct metabolic signature of liver metastases when compared to that of its associated primary PDAC. We are now exploring the environmental conditions, genetic events and signaling cascades leading to the metabolic reprogramming of metastatic tumor cells.

Targeting tumor lipid dependence for therapeutic and diagnostic purpose (leader of the project : Guillaumond Fabienne)

Over the last years, through combination of transcriptomic, proteomic and lipidomic approaches, we showed that lipid metabolic pathways are highly altered in PDAC compared to the normal pancreas. We currently focus on several lipid pathways found upregulated in aggressive PDAC and search for their contribution to the progression of the tumor from early to late stages of the pathology. We previously found that catabolism of lipoproteins, such as LDL, is crucial to supply tumor cells with cholesterol. We demonstrated that cholesterol uptake through the LDL receptor (LDLR) is the main pathway used by tumor cells to satisfy their excessive needs of cholesterol.

Additionally, we showed that targeting LDLR in combination with chemotherapy decreases PDAC burden and improves the efficacy of chemotherapy routinely used in clinic. Moreover, clinically, increased activation of several lipid pathways is not restricted to a tumoral stage, and LDLR expression is correlated with an increased risk of tumoral recurrence (F. Guillaumond et al. Proc Natl Acad Sci U S A 2015). We are now looking for lipid metabolic pathways, so far uncovered as promoters of pancreatic carcinogenesis, in order to expand the target panel useable to tackle the lipid dependency of PDAC.