Team 5 – Research themes

NEWS

JPArc Séminaire 22 mars 2018
équipe mucines, différenciation cancérogenèse épithéliales

MUCINS, EPITHELIAL DIFFERENTIATION AND CARCINOGENESIS TEAM

RESEARCH THEMES

A- Role of MUC1, MUC4 mucins in epithelial carcinogenesis

A.1- Role of MUC1 and MUC4 mucins in pancreatic, oeso-gastric, colonic and renal carcinogenesis. In vitro (2D, 3D, organoids cellular models), in vivo (transgenic mice, cell and PDX xenografts) and ex vivo (patient material) models.

A.2- Study of the structure-function relationship of MUC4-ErbB2 complex and of MUC1-CT cleavage site. Therapeutic targeting and discovery of new medicine drug candidates.

B- Study of molecular mechanisms responsible for tumor resistance/recurrence

B.1- Deciphering of resistance mechanisms to chemotherapy and drug escape (tumor dormancy, cellular reprogramming). Role and plasticity of cancer cells (epigenetic mechanisms: DNA methylation, histone code, noncoding RNA, metabolism, stemness).

B.2- Transversal/translational research with hospital partners: Search for prognostic (identification and classification of tumors) and predictive (therapeutic orientation, patient management) markers/factors. Comparison of primary tumor/recurrence/metastasis. Molecular cartography of tumors.

Role of MUC4 in pancreatic adenocarcinoma and tumor resistance (Principal Investigator: Dr Nicolas Jonckheere)

Pancreatic Ductal Adenocarcinoma (PDAC) cancer is the 4th leading cause of death by cancer in the world with an extremely low survival rate (6 months) and a short survival curve at 5 years (3%). Our project aims to understand the roles of the membrane bound mucin MUC4 and its partner, the oncogenic receptor ErbB2 and the cellular underlying mechanisms (cell signaling, miRNA) in pancreatic carcinogenesis (Dr Jonckheere). We are using a triple (in vitro, in vivo and ex vivo) approach to decipher their roles in the initiation of pancreatic carcinogenesis and in the resistance to chemotherapy. We also develop a structure-function project (Dr Van Seuningen) aiming at targeting MUC4-ErbB2 oncogenic complex via MUC4 EGF domains and develop small inhibitory therapeutic molecules in collaboration with chemists (Dr Lebègue, ONC team of JPARC & Faculty of Pharmacy). 4D microfluidic devices (Dr Van Seuningen), at the interface between in vitro cell culture models and in vivo murine models, are also developed in collaboration with Dr Senez (IEMN, Villeneuve d’Ascq) to study tumor-stroma interactions and drug resistance.

Group members:

Publications: see list of publications.

Collaborations:

Local:

  • Pr Isabelle Fournier, Dr Maxence Wisztorski. Inserm U1192/PRISM, Villeneuve d’Ascq. MALDI-MSI cartography of tumors combined to microproteomics.
  • Dr Vincent Senez, UMRCNRS/IEMN, Villeneuve d’Ascq. Setting-up of 4D organ-on-chip microfluidic devices to study drug resistance and tumor-stroma interactions.
  • Pr Nadira Delhem, Dr Olivier Morales, UMRCNRS 8161/Institut de Biologie de Lille. Galectin-9, exosomes and pancreatic cancer.
  • Dr Nicolas Lebègue, Inserm UMR-S 1172, JPARC équipe “Onco et Neuro-chimie”, Lille. Development of small molecules inhibiting MUC4-ErbB2 complex.

National:

  • Pr Halima Ahidouch Ouadid, Dr Mathieu Gautier. Laboratoire de Physiologie Cellulaire et Moléculaire – EA4667, Amiens. MUC4-TRPM7/KCNN4 ion channel interactions.
  • Dr Jérome Torrisani, Inserm U1037/CRCT, Toulouse. MUC4-miRNA and pancreatic cancer.

International:

  • Pr Patrick Jacquemin, Université Catholique de Louvain, De Duve Institute, Bruxelles, Belgique. Mucins and pancreatic cancer.

Fundings:

  • 2017 Ligue contre le Cancer Comité 60 (NJ): MUC4-TRPM7/KCNN4 ion channel interactions.
  • 2016-17 Ligue contre le Cancer Comité 62 (NJ): MUC4 and chemoresistance in pancreatic cancer.
  • 2015-17 SIRIC ONCOLille (NJ): MUC4 and chemoresistance in pancreatic cancer.
  • 2016-2018 ANR DRUG_MUC4 (IVS): Therapeutic targeting of MUC4-ErbB2.
  • 2017-2019 LNCC CD62 (IVS): Therapeutic targeting of MUC4-ErbB2.
  • 2013-2017 SIRIC ONCOLille (IVS): Therapeutic targeting of MUC4-ErbB2.

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MUC1, renal cancer and renal fibrosis (Principal Investigator: Dr Michaël Perrais)

MUC1 is a large glycoprotein transmembrane mucin that is expressed at the apical surfaces of normal epithelia but also in hematopoietic and human embryonic stem cells. We focus our attention on its roles in kidney since MUC1 is expressed in convoluted distal tubules and collecting ducts. We develop two-research axis:

  • In renal cancer, MUC1 is overexpressed and increased migration, proliferation and invasion of renal cancer cells. Now, we study the roles of MUC1 in chemoresistance.
  • In renal non-cancerous diseases, we have shown a dual role of MUC1 in ischemia-reperfusion injury: Nephroprotector in early phase, but pro-fibrotic in late phase. We study MUC1 roles in kidney by using other mice models.

 

Group members:

Publications: see list of publications.

Collaborations:

  • Dr C. Cauffiez et Dr N. Pottier (EA4483, Université de Lille), Pr F. Glowacki (Service de Néphrologie, CHRU de Lille): MUC1 and non cancer renal pathologies.
  • Dr S. Lancel (UMR 1011, Lille): MUC1 and mitochondrial metabolism.
  • Dr D. Blum (UMRS 1172/JPARC, Team “Tauopathies”, Lille), Dr C. Cauffiez (EA4483, Lille): Lung cancer and A2AR.

Fundings:

2018: Cancéropôle Nord-Ouest: MUC1-CT therapeutic targeting.
2016-2017: Ligue Nationale contre le Cancer Comité du Nord : MUC1-CT cleavage.

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Tumor resistance and oesogastric cancers (Principal Investigator: Dr Florence Renaud)

Oesophageal and gastric cancers are spontaneously resistant tumours to loco-regional treatments, with a poor global overall survival of 15% at 5 years.

The Lille center benefits from high level of expertise of clinical care and research based on a local structuration through the Integrated Research Center (SIRIC ONCOLille, (SIRIC ONCOLille, www.oncolille.fr) and national structuration with the French Research Esophageal and Gastric Tumours working group (FREGAT network, www.fregat-database.org), as well as numerous collaborations worldwide.

The overall objective of these patient-centered research programs are to (I) standardize practices based on a high level of care (II) optimize therapeutic strategies through a patient and tumour personalized approach, (III) decrease treatment-related aggressiveness, (IV) develop innovative therapies and treatment plans.

Our research program (clinical, translational and basic science) is more particularly focused on tumor resistance, and poorly cohesive cells carcinoma.

 

Group members:

Publications: see list of publications.

Fundings:

2017

  • Bonus H (CHRU Lille): Translational study of primary tumor/recurrence comparison in oeso-gastric cancers.
  • SIRIC ONCOLille: Translational study of primary tumor/recurrence comparison in oeso-gastric cancers.

2016

  • Fonds Hospitaliers CHRU Lille: REComics project.
  • GIRCI Jeune Chercheur: REComics project.
  • SIRIC ONCOLille: RECIMET project.
  • SIRIC ONCOLille: PROMOREC project.
  • PHRC (INCa): French participation to an international phase III clinical trial.

2015

  • Ligue Nationale Contre le Cancer (comité du Nord): Caracterisation of gastric cancers with independent cells.
  • FREGAT SIRIC ONCOLille.
  • PHRC (INCa): French phase III clinical trial.

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Colon cancer cells and metastatic recurrence (Principal Investigator: Dr Guillemette Huet)

Our group studies the phenotype and functional properties of colon cancer stem cells resistant to chemotherapies and responsible for metastatic tumor recurrence. Our aim is to identify metabolic signals involved in cellular reprogramming of cancer cells into colon cancer stem cells with drug resistance and metastatic properties. Our work combines metabolomics and cellular approaches, in particular mass spectrometry, flow cytometry and cellular imaging, on isolated cells and human samples of liver metastases.

Group members:

Publications:  see list of publications.

Fundings:

2018-2020: Ligue Nationale contre le Cancer (Comité du Nord): Colonic cancer cells and metastatic relapse.

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Galectin-3, cancer and mRNA life cycle (Principal Investigator: Pr Pascal Pigny)

Discovery of a new function of the galectin-3, consisting in the control of the mRNA half-life of the human mucin MUC4 in cancer cells. This is based on a synergistic effect with hnRNP-L, a RNA binding protein that interacts with the 3 ‘ UTR of MUC4. Our data suggest that Galectin-3 is co-localized with hnRNP-L and MUC4 mRNA in the cytoplasmic RNA granules, where mRNAs are maintained in the untranslated state. We are currently looking for a more global effect of galectin-3 by determining all the mRNAs whose half-life is affected by this endogenous lectin.

Group members:

Publications: see list of publications.

Fundings:

2018-2020: Ligue Nationale Contre le Cancer (comité de la Somme): Role of galectin-3 in cancer.

Collaborations:

National:

  • Dr Delphine Delacour, team Adhésion cellulaire et mécanique, UMR CNRS 7592, Institut Jacques Monod, Paris.
  • Dr Sébastien Leon, team Trafic membranaire, ubiquitine et signalisation, UMR CNRS 7592, Institut Jacques Monod Paris.
  • Dr Cyrille Grandjean, team Ingénierie moléculaire et glycobiologie, UMR CNRS 6286, Université de Nantes.

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Epigenetics and cancer stem cell plasticity (Principal Inverstigator: Dr Audrey Vincent)

We focus on studying the epigenetic mechanisms (DNA methylation, histone post-translational modifications) that drive cancer cell plasticity and hence the innate or acquire capacity of cancer cell to switch on and off stem cell properties (self-renewal, asymetric division, pluripotency). To this aim, we are working on two different cancer models: the colon and the pancreas, developing new tools such as 3D primary cellular models through the collaboration of clinicians, chemists and physicians. This multidisciplinary approach allows us to better understand cancer stem biology.

Our objectives are to:

(1) Identify the epienzyme complexes that are involved in stem cell properties in colon cancer cells in order to find more specific epidrugs,

(2) Identify new epigenetic targets that would drive cancer cell “differentiation” through epigenome editing,

(3) Identify molecular cancer subtypes that would benefit from epidrug treatments, and

(4) Identify epienzymes that are involved in acquired chemoresistance of pancreatic cancer cells in order to restore chemosensitivity through epidrug treatments.

 

Group members:

Publications: see list of publications.

Fundings:

  • 2017: Cancéropôle Nord Ouest “Projet émergent”. Epigenetics and cancer stem cell plasticity .
  • 2014, 2016: Comité du Nord et comité de l’Oise de la Ligue contre le Cancer. Epigenetics and cancer stem cell plasticity.

Collaborations:

National and international (in relation with project):

  • IEMN, Groupe BioMEMS, Lille, France. Dr Vincent Senez.
    Setting up of a 3D microfluidic device to study epigenetic mechanisms of reprogramming involved in plasticity of colonic stem cells.
  • Inria, MODAL, Lille, France. Dr Guillemette Marot.
    Integrated bioinformatic and biostatistic analyses of transcriptomic and epigenomic data.
  • JPArc, Équipe “Neuro-Oncochimie” du Pr Patricia Melnyk, Lille, France. Pr Philippe Cotelle.
    Design of new specific chemical inhibitors of epienzymes.

Others:  local, national and international:

  • INSERM U1019-CIIL, Lille, France. Dr Mathias Chamaillard.
    Influence of the microbiota on epigenetic mechanisms driving intestinal and colonic epithelial cell differentiation.
  • UMR CNRS 8576, Villeneuve d’Ascq, France. Dr Anne Harduin-Lepers.
    Study of glycosyltransferase regulation along the intestinal crypt-villus axis.
  • Toxalim UMR INRA 1331, Toulouse, France. Dr Muriel Mercier-Bonin.
    Study of the effect of alimentary toxins on intestinal barrier.

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Impact of long non-coding RNAs on cellular behaviour and properties of cancerous cells (Principal Investigator: Dr Bernadette Neve)

Long non-coding (lnc) RNAs, are a heterogeneous class of RNAs without protein-coding sequence that are arbitrary defined as non-coding RNAs over 200 nucleotides long. Accumulating evidence shows that lncRNAs are involved in the initiation, progression and metastasis of cancer (Yan et al. 2015; Li et al. 2016; Terracciano et al. 2017).

Our research objectives are:

1) To identify the critical LncRNAs associated with chemoresistance and cell survival in colorectal cancer cells. Colorectal cancer still has a high mortality rate (17,000 deaths per year). According to diagnosis at an early or late stage with metastases the 5-year survival rate ranges from 94% to 5%, respectively. This demonstrates the need for discovering new prognostic markers. We will use CRISPR/Cas9 to invalidate and study how the lncRNAs affect cellular behaviour.

2) To analyse the lncRNA’s function in cancerous processes. The specific mechanisms by which lncRNAs modify the cellular processes involved in cancer can be diverse (Rao et al. 2017; Sun et al. 2017). It has been shown that lncRNAs can directly control gene expression through multiple mechanisms regulating transcription in the nucleus (chromatin remodelling, transcriptional control, alternative splicing), they can interfere with protein degradation and function, and they can also be miRNA precursors or act as competing-endogenous RNA (ceRNA).

3) To validate the lncRNA’s clinical relevance in human tumours. Using tumour samples available at the CHRU of Lille (digestive surgery service; Pr S. Truant, Pr F.R. Pruvot), we will examine the expression of relevant LncRNAs (qPCR /in situ RNA detection) in primary tumours and in hepatic metastasis.

 

Group members:

Publications: see list of publications.

Fundings:

Ligue Nationale Contre le Cancer CD59 (2017-2018).

Collaborations:

  • Dr. Michel Wassef (Wassef et al. Methods 2017), Institut Curie/UMR3215/U934, Paris
    Generation of reversible “knockouts” (R-KO) using CRISPR/Cas9.
  • Pr Halima Ahidouch-Ouadid, Dr Mathieu Gautier, LPCM – EA4667, Amiens
    Generation of TRPM7 constructs using crispr-cas9.

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