Molecular determinants of treatment response in Triple Negative Breast Cancers

Job title:

Molecular determinants of treatment response in Triple Negative Breast Cancers

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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), OncologyKeywords: Triple Negative Breast Cancer, ImmunotherapyResearch project descriptionBackgroundTriple-negative breast cancers (TNBC) account for 10 to 20% of all breast cancers but have the worst prognosis and affect younger women who relapse faster. This aggressive behavior is due to rapid growth, a strong tendency to metastasize, and the lack of targeted therapy because of this subtype heterogeneity. Whilst immunotherapy is now part of the standard of care for most TNBC tumors, there is a clear need to identify reliable biomarkers to stratify patients likely to benefit from immunotherapy. With this project, the applicant will identify and validate key molecular determinants of the tumor escape to immunotherapy.Working hypothesis and aimsRecent clinical studies have highlighted that the correlation between PD-L1 expression (the only currently used biomarker) and patients’ responsiveness to PD1/PDL1-targeting-immunotherapy is poor in TNBC (Miles et al, 2021). Preclinical data and our preliminary results suggest that some of the additional potential determinants of immunotherapy response include a modulation of the antigenicity of tumor cells as well as a regulation of their ability to escape immune system-induced cell death (Djajawi et al, 2023). The project aims to define, amongst the several factors which could determine this antigenicity and responsiveness to cell death, those that are the most relevant in TNBC immunotherapy response.Scientific objectives of the projectThe objectives of the project will include but are not limited to: i) Establishing, using literature and biological databases mining, a list of candidate genes that modulate tumor cell antigenicity and/or tumor cell death. ii) Assessing the relevance of these candidates in relapse using transcriptomic (RNA seq) and IHC approaches using both in-house and publicly available databases of TNBC tumors.iii) For the most relevant candidates (or a combination thereof), exploring the molecular mechanism underlying their role in immunotherapy response using human and murine TNBC cell lines as well as two syngeneic mouse models of TNBC, all already routinely used in the host laboratory.iv) Participating in the establishment of a prospective collection of fresh frozen and FFPE-embedded primary TNBC tumors and evaluate the role of the identified determinants in clinical response to immunotherapy. The Postdoctoral fellow will work with a clinician and benefit from the technical expertise of the team for both wet lab approaches (cell culture, biochemistry, cell biology, in vivo experiments) and bioinformatic analyses. Input from the postdoctoral fellow on the project design and methodology will be expected.References:– Djajawi TM, Wichmann J, Vervoort SJ & Kearney CJ (2023) Tumor immune evasion: insights from CRISPR screens and future directions. FEBS J– Lafont E, Draber P, Rieser E, Reichert M, Kupka S, de Miguel D, Draberova H, von Mässenhausen A, Bhamra A, Henderson S, et al (2018) TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation. Nat Cell Biol 20: 1389-1399– Lafont E, Kantari-Mimoun C, Draber P, De Miguel D, Hartwig T, Reichert M, Kupka S, Shimizu Y, Taraborrelli L, Spit M, et al (2017) The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death. EMBO J 36: 1147-1166– Le Gallo M, O’Hara AJ, Rudd ML, Urick ME, Hansen NF, O’Neil NJ, Price JC, Zhang S, England BM, Godwin AK, et al (2012) Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatinremodeling and ubiquitin ligase complex genes. Nat Genet 44: 1310-1315– Miles D, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios C, Xu B, Wardley A, Kaen D, Andrade L, et al (2021) Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol 32: 994-1004– Pelizzari-Raymundo D, Maltret V, Nivet M, Pineau R, Papaioannou A, Zhou X, Caradec F, Martin S, Le Gallo M, Avril T, et al (2024) IRE1 RNase controls CD95-mediated cell death. EMBO RepSupervisorsThe Postdoctoral Fellow will be supervised by Dr Elodie Lafont and Dr Matthieu Le Gallo.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, for example (Lafont et al, 2018, 2017) during her post-doc, and more recently through modulation of the IRE1-mediated ER stress response (Pelizzari-Raymundo et al, 2024). 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 Matthieu Le Gallo has expertise in cell biology and immunology, with specific training and expertise in cancer genomics, which he developed during his post-doctorate at NIH, participating in the first characterization of genomic alterations in aggressive endometrial tumors (Le Gallo et al, 2012). His current work builds on these “omics” approaches to characterize the effect of the immune microenvironment on treatment response in aggressive breast cancer subtypes. He co-directed 3 PhD students (2 ongoing and 1 who defended in 2021).DepartmentU1242 is an INSERM laboratory located in the 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 signalling pathways in solid tumours (including TNBC). The unit is composed of four teams, and the proposed project is at the intersection of the work led by Dr Le Gallo from the bioinformatics team @tomics and by Dr Lafont from the Proteaostasis and cancer team. The applicant will have access to all relevant services (either locally or through collaborations) and in particular to transcriptomics and spatial mass spectrometry (samples, IHC, hyperion, RNAseq, cell culture…). Dr Le Gallo and Dr Lafont are recipients of local, national, and European fundings. This for example includes different patient associations like La Vannetaise ou La Josselinaise, national funding bodies like La Ligue contre le Cancer, Fondation de France and Fondation ARC contre le Cancer, as well as the European program H2020-MSCA-RISE-2017 #777995DISCOVER,RequirementsResearch Field Biological sciences Education Level PhD or equivalentSkills/QualificationsSpecific Skill Requirements:Required: Cell culture, biochemistry, and molecular biology bases (western blot, ELISA, cloning, RT-qPCR, immunoprecipitation, protein purification), geneediting (e.g. base-editing, CRISPR).Previous animal work will be a plus.Basic knowledge of Unix and R would be a plus but is not required.Any additional expertise will be a plus.Required Languages:English (fluent)Other skills required:Since the applicant will be working with different teams, including with a clinician PhD student, ability to work as a team, communication skills and benevolence are crucial.Publications:The applicant must have at least one first author publication in a recognized peer-reviewed international journal from each of their research experiences (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-Mail[email protected]STATUS: EXPIRED

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Location

France

Job date

Sun, 31 Mar 2024 02:35:07 GMT

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