UMRS 938 - Hôpital Saint-Antoine 34, Rue Crozatier
A funded post-doctoral position is opened in the ‘Microsatellite and Cancer’ team headed by Alex Duval (UMRS 938, Inserm, Saint-Antoine Hospital, Paris).
Presentation of the Research team and Scientific/clinical environment:
The ‘Microsatellite Instability and Cancer’ research team has been created on January 1st, 2006. It is located in the center of Paris, in the Saint-Antoine Research Centre (Saint-Antoine Hospital). The topics for this research lab are focused on the study of mismatch repair (MMR)-deficient human tumors displaying microsatellite instability (MSI). Since funded, this lab has established an extensive clinical and research network, leading to the development of an ambitious research program focused on cancer genetics. It published widely on MSI tumors in high-ranked basic and clinical journals. In 2018, the SIRIC CURAMUS led by the AP-HP-Pitié-Salpétrière and HUEP (Saint-Antoine, Tenon, Trousseau) has been founded in the East of Paris. The investigation of MSI tumors has been integrated as one of the three major research programs of CURAMUS because MSI cancers cover a broad range of frequent hereditary or sporadic tumors sharing common biological mechanisms and requiring increasing needs for personalized medicine.
Context and Job description :
The MSI-driven pathway to cancer leads to the synthesis of aberrant and potentially immunogenic neo-antigens by the tumor cells. A likely consequence is that MSI tumors are highly infiltrated with cytotoxic T-cell lymphocytes (CTLs) that are thought to constitute strong and independent predictors of relapse and survival in tumors regardless of their molecular phenotype (MSI or MSS). Recently however, it was shown that MSI tumors were likely to persist in such an hostile immune microenvironment because of immune-escape due to dramatic co-overexpression of immune checkpoint (ICK)-related proteins. Based on these findings, MSI status was shown to predict clinical benefit from ICK blockade therapy with an anti-PD-1 inhibitor in a fraction of patients with metastatic neoplasm. Recent analysis of the expression level of genes encoding ICK in two independent cohorts of CRC treated with standard care (stage 1 to stage 4 CRC; 232 MSI, 971 MSS) in our team highlighted that ICK overexpression was associated with significantly worse prognosis in MSI tumors only (e.g. not in MSS CRC), independently of tumor staging or CTL infiltrates (Immunoscore).
As a project, the candidate will aim to further establish how the immune contexture of MSI tumors has a crucial role during MSI tumorigenesis from both a pathophysiological and clinical point-of-view. In particular, he/she will try to better design the exact perimeter of future immunotherapy involving antibody blockade of ICKs and resistance to these molecules in MSI CRC patients. Several large retrospective but also prospective cohorts (MOSAIC/IDEA clinical trial) of MSI/MSS CRC patients including stage 3 or stage 4 tumors treated by standard care (untreated with immunotherapy) are already available for the project, and also stage 4 MSI CRC treated with immunotherapy (Ac anti- PD-1 +/- anti- CTLA-4) within the context of a Clinical trial (NIPICOL) coordinated by the team. Somatic mutational events and those participating to the so called MSI-driven mutational events that frequently accumulate in MSI tumor cells and deeply influence anti-tumor immunity and the expression of ICK molecules will be assessed by exploiting both Exome and RNA sequencing data that are already available for the project (e.g. mutations affecting neo-antigens presentation by tumor cells, …).
We are seeking a post-doc candidate with strong experience in high-throughput data analysis.
Contact details :
Please contact Alex Duval (e-mail : email@example.com & firstname.lastname@example.org).
When applying, please ensure you include a CV, motivation letter, list of publications and the names and addresses of at least two persons as references.
10 selected recent publications from the team :
Bouvet D, Bodo S, Munier A, Guillerm E, Bertrand R, Colas C, Duval A, Coulet F, Muleris M. Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. Gastroenterology. 2019 Aug;157(2):421-431. IF 20.3
Cohen R, Hain E, Buhard O, Guilloux A, Bardier A, Kaci R, Bertheau P, Renaud F, Bibeau F, Flejou JF, Andre T, Svrcek M, Duval A. Association of Primary Resistance to Immune Checkpoint Inhibitors of Metastatic Colorectal Cancer with Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status. JAMA Oncol. 2019. IF 20.5
Marisa L, Svrcek M, Collura A, … Ghiringhelli F, de Reynies A, Duval A. The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors. J Natl Cancer Inst. 2018 Jan 1;110(1). doi: 10.1093/jnci/djx136. PMID: 28922790 and European Patent. Application number EP15307157.6. IF 13
Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine JM, Cao ZA, Kamble S, Kopetz S, André T. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018 Mar 10;36(8):773-779. doi: 10.1200/JCO.2017.76.9901. Epub 2018 Jan 20. IF 23
Lupinacci RM, Goloudina A, Buhard O, …, Iovanna J, Duval A*, Svrcek M* (co-leadership). Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. Gastroenterology. 2017 Nov 17. pii: S0016-5085(17)36366-7. doi: 10.1053/j.gastro.2017.11.009. [Epub ahead of print]PMID: 29158190. IF 18.7
Bodo S, Colas C, Buhard O, …, Wimmer K, Muleris M, Duval A; European Consortium C4CMMRD. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. Gastroenterology. 2015 Oct;149(4):1017-29.e3. doi: 10.1053/j.gastro. 2015.06.013. Epub 2015 Jun 25.PMID:26116798 and European Patent. Application Number EP11305160.1. IF 18.7
Andre T, de Gramont A, Vernerey D, …., Duval A, Fléjou JF, de Gramont A. (2015) Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol 2015 33: 4176-87. IF 20
Collura A, Lagrange A, Svrcek M, …, Fléjou JF, Garrido C, Duval A. Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy. Gastroenterology. 2014 Feb;146(2):401-11.e1.PMID:24512910 and European Patent. Application Number EP11305330.0. This patent is exploited by the company QIAGEN (exclusive license). IF 18.7
Berthenet K, Boudesco C, Collura A, Svrcek M, Richaud S, Hammann A, Causse S, Yousfi N, Wanherdrick K, Duplomb L, Duval A*, Garrido C*, Jego G* (co-leadership) (2016) Extracellular HSP110 skews macrophage polarization in colorectal cancer. Oncoimmunology 5: e1170264. IF 7.5 Dorard C, de Thonel A, Collura A, …, Gaub MP, Garrido C, Duval A. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nat Med. 2011 Sep 25;17(10):1283-9. doi: 10.1038/nm.2457.PMID:21946539. IF 29