Relevance of Dual IRE1 Targets in cancer: a bioinformatical approach (DIT-CAN-BIOINF)

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Relevance of Dual IRE1 Targets in cancer: a bioinformatical approach (DIT-CAN-BIOINF)

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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, machine learning, multi-omics integration, network analysis.Keywords: ER stress, cancer, IRE1, RNA biology, cell signaling, gene networks.Research 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. We previously identified a molecular signature reporting IRE1 activity in tumors. However, it is not an efficient predictor of the response to IRE1i in preclinical models, justifying the refinement of this signature. 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) (PMID: 38153426 and PMID: 38383861). 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 identify more globally the DIT and establish a novel gene signature associated with IRE1 activities to better stratify cancer patients. We also aim to define the molecular features and cellular functions of DIT and to assess the clinical relevance of DIT in cancer.– Scientific objectivesThe post-doctoral fellow work will address the following objectives:i) Identify the DIT using local and public datasets;ii) Determine whether the DIT are associated with particular cellularcomponents, biological and molecular functions;iii) Evaluate whether the DIT (as a whole, sub-groups or individual genes) are associated with therapy response, relapse and survival in different types of human cancers for which IRE1 activation is either positively or negatively correlated with prognosis;iv) Define whether DIT display specific RNA sequence/structure and their promoter specific sequences;v) Define whether the DIT are part of/could be involved in controlling genenetwork evolution during ER stress;vi) Define whether the DIT are correlated with the previously defined XBP1s/RIDD signature in various cancer;vii) Define whether the DIT may constitute predictive factors to IRE1 inhibition in pre-clinical models of TNBC and GBSupervisorsThe Postdoctoral Fellow will be supervised by Dr Tony Avril and Dr Marc Aubry.Dr Marc Aubry is a Research Engineer of the Rennes University and a Principal Investigator at the U1242 research unit. He has two Master’s Degrees, one in evolutionary biology and the other in informatics. Since completing his PhD in bioinformatics, he has tackled intra-tumoral heterogeneity of cancer cells (with a focus on GB) through integrative approaches (PMID: 25940437, 19154582). He is also interested in exploring the (epigenetic) mechanisms mediating the cellular plasticity of those cells (PMID: 38302900, 21156036). He has supervised 9 Master students and he is co-supervising 1 PhD student.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, involved in NFkB activation and chemokinesmediated 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 (Dr Tony Avril) and the bioinformatics @OMICs team (Dr Marc Aubry). The applicant will have access to all relevant services (either locally or through collaborations) and in particular to the HPC resources (Cloud, Docker, Slurm) provided by the Genouest and IFB Core Cluster facilities and to all of the methods already developed in the lab and stored in a dedicated GitLab. Dr Avril and Dr Aubry are recipients of local, national and European fundings. This for example includes different patient associations like Oligocyte, regional funding like l’Institut de Neurosciences Cliniques de Rennes, national funding bodies like La Ligue contre le Cancer, Fondation de France and Fondation ARC pour la recherche sur le Cancer. Dr Avril and Dr Aubry have also contributed to the work performed as part of the European programs EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED).RequirementsResearch Field Other Education Level PhD or equivalentSkills/Qualifications– Required: Mastery of general machine learning models (insufficient data available to apply neural networks models) and a strong expertise in multi-omics data integration. Knowledge of the main statistical network analysis methods 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 INSERM/ Université de Rennes U1242, Oncogenesis Stress Signaling laboratory, Country France GeofieldWhere to apply WebsiteContact WebsiteE-Mailcontact@2PE-bretagne.euSTATUS: EXPIRED

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Location

France

Job date

Sat, 30 Mar 2024 23:57:34 GMT

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