Early Stage Researcher (ESR/PhD) in the Marie Skłodowska-Curie ITN European Training Network “TRANSMIT – TRANSlating the role of Mitochondria in Tumorigenesis” (H2020-MSCA-ITN-2016) - ESR 5 (University of Bologna, DIMEC, Italy)
TRANSMIT - TRANSlating the role of Mitochondria in Tumorigenesis
The consolidation of the knowledge that cancer is not only a genetic, but also a metabolic disease, has led scientists to investigate the intricate metabolic plasticity that transformed cells must undergo to survive the adverse tumor microenvironment conditions, and the contribution of oncogenes and tumor suppressors in shaping metabolism. In this scenario, genetic, biochemical and clinical evidences place mitochondria as key actors in cancer metabolic restructuring, not only because these organelles have a crucial role in the energy and biosynthetic intermediates production but also because occurrence of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA has been associated to different types of cancer. TRANSMIT aims to dissect the metabolic remodeling in human cancers, placing the focus on the role of mitochondria and bridging basic research to the improvement/development of therapeutic strategies. Further, TRANSMIT fosters the communication of this emerging field to the patients and their families. To these aims, TRANSMIT will create a network of seven different countries, among which world-leading basic science and clinical centers of excellence, several industrial partners with up-todate omics technologies, as well as non-profit foundations and associations who care for cancer patients. By creating the critical mass of scientific excellence, TRANSMIT will allow to transfer the current knowledge into the wide field of cancer research, translating scientific and technical advances into the education and training of eleven Early Stage Researchers. TRANSMIT will implement training-through-research dedicated to unravel the metabolic features of cancer, as well as to provide a full portfolio of complementary skills through the creation of a network of basic, translational and industrial laboratories, devoted to a multidisciplinary/multisectorial education of young scientists.
1) Job Summary. The candidate will be enrolled in a PhD program to work in molecular oncology, learning and exploiting molecular genetics and biology techniques, to generate and characterize cancer cell models targeted for metabolic and tumor suppressor proteins, and test them for modifications in their tumorigenic potential, both in vitro and in nude mice models. Starting from the knowledge of the oncojanus function for respiratory complex I genes, the candidate will investigate the synthetic lethality of other molecular targets with such genes. In collaboration with other consortium partners and through secondments, the candidate will acquire knowledge of specific techniques to tackle the issues proposed. Collateral skills will be developed during the 3-years fellowship, such as grant and paper writing, fund raising abilities, outreach and dissemination in the field of molecular oncology.
2) Job description: Application refers to an Early Stage Researcher (ESR) position to be trained for 36 months at the Department of Medical and Surgical Sciences, University of Bologna, in the framework of the TRANSMIT project entitled “Mitochondrial complex I-driven regulation of the hypoxic response in cancer cells” (ESR 5). Supervisor: Prof. Giuseppe Gasparre.
Adaptation to hypoxia is one of the main features of aggressive cancer cells, a process mediated by the hypoxia-inducible factor 1α (HIF1α). During oxygen shortage, HIF1α becomes stabilized following inhibition of α-ketoglutarate (α-KG)-dependent prolyl-hydroxylases (PHDs). Therefore, α-KG levels are critical in the cell capacity to respond to hypoxia through HIF1α, which acts as a key transcription factor to transcribe a large set of genes involved in the upregulation of glycolysis, promotion of neoangiogenesis and metastasis. In turn, α-KG dehydrogenase (α-KGDH) is regulated by NADH levels, the main substrate of CI. Tumors in which CI is mutated and disassembled, such as benign oncocytomas, are unable to respond to hypoxia and progress to malignancy due to their lack of NADH consumption and consequent accumulation of α-KG. To translate these findings into a potential adjuvant therapeutic strategy, and to deeply dissect the biochemical mechanisms linking CI disruption to hypoxia adaptation, the candidate will use genome editing approaches such as Zinc Finger Nucleases or CRISPR technology to generate knock-out (KO) clones for CI subunit NDUFS3, essential to assemble CI, starting from cancer cell models such as osteosarcoma 143B, colon HCT116 and ovary SKOV-3, whose growth kinetics in nude mice are known. The candidate will hence characterize clones for NADH and α-KG accumulation following CI disruption and will attempt to reconstruct the metabolic routes used by the KO clones to survive, via metabolomics analyses. The candidate will exploit a hypoxic chamber to challenge KO clones to forcedly respond to hypoxia and will assess by western blot whether they are able to trigger HIF1α stabilization. Clones will be challenged for their anchorage-independent growth ability in soft agar, and subsequently the candidate will proceed to observe whether KO clones are able to form xenografts in nude mice. The hypoxia level of xenograft will be evaluated with pimonidazole, whereas HIF1α stabilization in vivo will be assessed by immunohistochemistry and western blot. Moreover, the candidate will have available a syngenic HCT116 cell line devoid of tumor suppressor TP53, whose role in mitochondrial metabolism regulation is well known to act through TP53-induced glycolysis and apoptosis regulator and respiratory complex IV (31). The candidate will obtain NDUFS3 knock-out of p53-null HCT116 to compare with p53-competent HCT116, to unravel the metabolic rewiring occurring in the absence of a pivotal tumor suppressor gene. The candidate will attempt to understand whether the anti-tumorigenic effect of NDUFS3 KO may be overcome by the abolishment of p53.
3) Subject area of PhD program in which the ESR will be enrolled and PhD program duration: Medical, Pharmaceutical and Veterinary Medical Sciences; PhD in General Medical Sciences (duration 3 year)
4) Host University that will provide the PhD degree: Università di Bologna, Italy- Department of Medical and Surgical Sciences.
5) PhD program starting date: November 1st 2017
Required Educational Level
Degree: Biology, Biotechnology, Genetics, Biochemistry, Medicine
Degree Field: Human Molecular Biology, Human Biology, Human Molecular Genetics, Human Genetics
Skills: Basic molecular biology and genetics techniques
Languages: Applicant should be fluent in written and spoken English
Applications, in English, should include CV, detailed academic transcripts, the abstract of the thesis (300 words max), a motivation letter, a reference letter and the application form, which are all to be submitted by email to Prof. Giuseppe Gasparre (firstname.lastname@example.org). Applicants are required to indicate both the title and the number of the project as the object of the e-mail (they are both mentioned in the "Job description" section).
Application deadline: June 18th 2017
The application form can be download from the following webpage: https://euraxess.ec.europa.eu/jobs/199795 by clicking on the "WHERE TO APPLY” section.
The applicant may be a national of a Member State, of an Associated Country or of any other Third Country.
Career: At the time of recruitment, applicants are to have academic qualifications to access a PhD position and have to be in their first four years of their research careers and have not been awarded with a doctoral degree.
Applicants are required to have less than 4 years of full time research experience.
Mobility: At the time of recruitment, Applicants must not have resided in Italy for more than 12 months in the 3 years immediately prior to the recruitment date and not have carried out their main activity (work, studies, etc.) in that country.
· Enrollment in a PhD school in a specific area
· The selected candidate will be appointed under a 36-month full-time employment contract according to the Italian national legislation. The remuneration will be compliant with the rules of the ITN-MSCA Program. The gross amount for the benefit of the researcher includes:
a) Monthly living allowance: the amount is € 3,318.37 per month.
b) Mobility allowance: the amount is € 600,00 per month (€ 7.200,00/year).
c) Family allowance: a Family allowance of €500 per month will be paid to researcher with family. Family” is defined as persons linked to the researcher by (i) marriage, or (ii) a relationship with equivalent status to a marriage recognised by the national or relevant regional legislation of the country where this relationship was formalised; or (iii) dependent children who are actually being maintained by the researcher. The family status of a researcher will be determined at the time of their (first) recruitment in the project and will not evolve during the project lifetime.
The net amount results from deducting all compulsory social security contributions as well as direct taxes from the gross amount.
· A highly multidisciplinary, cross-cultural and competitive training program in the field of metabolism in cancer and molecular oncology
· Secondments and a specific training program
· Vacation days/year: 30 days/year in addition to November 1, December 8-25-26, January 1, 6, April 25, May 1, June 2. Easter and Easter Monday (they change each year)
First selection step: Curriculum evaluation. Numerical scores will be awarded for grading criteria such as study marks, duration of study, scientific publications in peer reviewed journals, reference letters. Only the admitted candidates will be contacted by e-mail for the second selection step.
Second selection step: Skype or face-to-face interview in which candidates will give a short presentation of their master thesis and of a scientific paper that they will receive three weeks before the interview.
Two weeks during September / October 2017