Job title:
Relevance of Dual IRE1 Targets in cancer (DIT-CAN)
Company:
Job description
Offer DescriptionThe Marie S. Curie Postdoctoral Fellowship (MSCA-PF) programme is a highly prestigious renowned EU-funded scheme. It offers talented scientists a unique chance to set up 2-year research and training projects with the support of a supervising team. Besides providing an attractive grant, it represents a major opportunity to boost the career of promising researchers.The INSERM/ Université de Rennes U1242, Oncogenesis Stress Signaling laboratory, is thus looking for excellent postdoctoral researchers with an international profile to write a persuasive proposal to apply for a Marie S. Curie Postdoctoral Fellowship grant in 2024 (deadline of the EU call set on 11 September 2024). The topic and research team presented below have been identified in this regardResearch field: Life Sciences (LIF),Oncology, Molecular Biology, Cellular BiologyKeywords: ER stress, glioblastoma, triple-negative breast cancer, IRE1, RNA biology, cell signalling, tumorigenesis, metastasis, immune microenvironmentResearch project description– State-of-the-artThroughout tumor development, tumor cells are subjected to various intrinsic and extrinsic stressors (e.g. DNA damage, nutrient deprivation) which can lead to a stress of endoplasmic reticulum (ER). Adaptation to these stresses involves in particular the activation of an ER stress sensor called IRE1α (IRE1). We and other have demonstrated that IRE1-dependent signaling regulates tumor progression in several type of cancers, including the poor-prognosis Triple Negative Breast Cancers (TNBC) and Glioblastoma (GB). For instance, we demonstrated (i) the involvement of IRE1 on GB development and (ii) the impact of IRE1 inhibitors (IRE1i) as adjuvant drugs to GB and TNBC standard of care in preclinical models. IRE1 mainly signals through its RNase domain by unconventionally splicing XBP1 mRNA (yielding the transcription factor XBP1s) and by degrading RNAs through Regulated IRE1-Dependent Decay of RNAs (RIDD). We recently identified a class of mRNA whose expression is directly under the control of XBP1s and RIDD and that are associated with GB and TNBC aggressiveness (e.g., UBE2D3 and CD95). Of note, both of these proteins impact the cross-talk between immune cells and tumor cells. Using IRE1-related public datasets and data obtained in the laboratory, we predict that about 10% of XBP1s targets are degraded through RIDD and coined such factors “dual IRE1 targets” (DIT).The aim of the current project is to define whether DIT are general regulators of the immune cell-tumor cell crosstalk and thereby important mediators of IREi efficiency in TNBC and GB.– Scientific objectivesThe post-doctoral fellow will focus on DITs expression of which is found as being positively or negatively associated with prognosis in TNBC and GB patients (bioinformatics analyses are currently ongoing in the lab).To test this hypothesis, the post-doctoral fellow work will address the following objectives:i) Validate that the putative DIT are indeed RIDD and XBP1s targets invarious GB and TNBC cell lines, basally and upon chemical (e.gtunicamycin), or more physiological (e.g nutrient deprivation, hypoxia,mechanical stress) stress induction;ii) Identify whether modulating the expression of DITs in GB and TNBCtumor cells impacts on key cellular processes, focusing on NK- and T-cellmediated cell death induction, secretion of chemo/cytokines, immunogenicity, chemoattraction and myeloid cell polarization;iii) Evaluate whether the expression of DITs varies temporally and spatially during tumor progression in dependency of IRE1 activity using in vivo pre-clinical models of GB and TNBC (using the imaging mass cytometry approach Hyperion);iv) Define whether the DIT signature could be used as a predictor of IREi efficiency in pre-clinical in vivo models of GB and TNBC.The Postdoctoral fellow will work benefit from the technical expertise of the team for both wet lab approaches (cell culture, biochemistry, cell biology, in vivo experiments) and will work in close collaboration with the bioinformatic team of U1242. Inputs from the postdoctoral fellow on the project design and methodology will be expected.SupervisorsThe Postdoctoral Fellow will be supervised by Dr Tony Avril and Dr Elodie Lafont.Dr Elodie Lafont is an INSERM Junior Principal Investigator (CRCN) at the U1242 unit in Rennes. She has a strong background in biochemistry and cellular biology Throughout her career, Dr Lafont has identified multiple molecular regulators of Death Receptors (CD95, TNFR1, TRAIL-R1/2)-mediated signalling, including through sphingolipid metabolism during her PhD, linear ubiquitination (PMID: 28258062 and PMID: 30420664) during her post-doc, and more recently through modulation of the IRE1-mediated ER stress response (PMID: 38383861). She has supervised 1 bachelor student, 8 Master students, 1 post-doctoral researcher and co-directed 2 PhD students (1 ongoing and 1 who defended in 2022). She is an associate editor for Journal of cellular and Molecular Medicine and a regular reviewer for several internationally-renowned journals.Dr Tony Avril is a Principal Investigator of the Eugène Marquis cancer center at the U1242 unit in Rennes. He has a strong background in GB cellular biology In the past years, Dr Avril focuses on IRE1-dependent regulation of GB cell functions including immune attraction and tumor cell migration. He has recently identified IRE1- dependent regulation of UBE2D3, an E2 ubiquitin-activating enzyme involved in NFkB activation and chemokines-mediated attraction of myeloid cells in GB (PMID: 38153426). He has supervised 25 Master students and co-supervised 3 PhD students (one ongoing that will defend in 2024) and 3 post-doctoral researchers. He is a regular reviewer for several internationally-renowned journals.DepartmentThe INSERM U1242 ‘Oncogenesis Stress Signaling’ is an INSERM laboratory located in the Eugène Marquis cancer center of Rennes. The U1242 laboratory focuses on the understanding, the identification of the clinical relevance and the pharmacological targeting of several cellular stress signaling pathways in solid tumors (including TNBC and GB). The unit is composed of four teams, and the proposed project is part of the Proteostasis and cancer (PROSAC) team. The applicant will have access to all relevant services (either locally or through collaborations) and in particular to tissue/cell culture facilities, real time Q-PCR, flow cytometry and Incucyte apparatus, as well as tumor specimens from Biobank. Dr Avril and Dr Lafont are recipients of local, national and European fundings. This for example includes different patient associations like La Vannetaise or Oligocyte, national funding bodies like La Ligue contre le Cancer, Fondation de France and Fondation ARC pour la recherche sur le Cancer. Dr Lafont and Dr Avril have also contributed to the work performed as part of the European programs H2020- MSCA-RISE-2017 #777995 DISCOVER, EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED).RequirementsResearch Field Biological sciences Education Level PhD or equivalentSkills/Qualifications– Required: Cell culture, Biochemistry and molecular biology bases (western blot, ELISA, cloning, RT-qPCR, immunoprecipitation, protein purification), gene-editing (e.g base-editing, CRISPR), flow cytometry.Previous animal work will be a plus, willingness to work with animals is required. Any additional expertise will be a plus.– Required Languages: English (fluent)– Other skills: Ability to work as a team, communication skills and benevolence are absolutely crucial.– Publications: The applicant must have at least one first author publication in a recognised peer-reviewed international journal from each of their research experience (e.g one from PhD, one from post-doc). If preprints are provided as an alternative, these will be considered.Languages ENGLISH Level ExcellentAdditional InformationEligibility criteriaAcademic qualification: By 11 September 2024, applicants must be in possession of a doctoral degree, defined as a successfully defended doctoral thesis, even if the doctoral degree has yet to be awarded.Research experience: Applicants must have a maximum of 8 years full-time equivalent experience in research, measured from the date applicants were in possession of a doctoral degree. Years of experience outside research and career breaks (e.g. due to parental leave), will not be taken into account.Nationality & Mobility rules: Applicants can be of any nationality but must not have resided more than 12 months in France in the 36 months immediately prior to the MSCA-PF call deadline on 11 September 2024.Selection processWe encourage all motivated and eligible postdoctoral researchers to send their expressions of interest through the EU Survey application form ( ), before 5th of May 2024. Your application shall include:
- a CV specifying: (i) the exact dates for each position and its location(country) and (ii) a list of publications;
- a cover letter including a research outline (up to 2 pages) identifying theresearch synergies with the project supervisor(s) and proposed researchtopics described above.
Estimated timetableDeadline for sending an expression of interest5 May 2024Selection of the most promising application(s)May – June 2024Writing the MSCA-PF proposal with the support of the above-mentioned supervisor(s)June – September 2024MSCA-PF 2023 call deadline13 September 2024Publication of the MSCA-PF evaluation resultsFebruary 2025Start of the MSCA-PF project (if funded)May 2025 (at the earliest)Website for additional job detailsWork Location(s)Number of offers available 1 Company/Institute The INSERM/ Université de Rennes U1242, Oncogenesis Stress Signaling laboratory Country France GeofieldWhere to apply WebsiteContact WebsiteE-Mail[email protected]STATUS: EXPIRED
Expected salary
Location
France
Job date
Sun, 31 Mar 2024 03:18:10 GMT
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