The Vall d´Hebron Institute of Oncology (VHIO) Seeks a “Post-doctoral Scientist for the Cancer Genomics Lab”
Reference: Ref. 51-2023
Application deadline: 15/11/2023
Number of vacancies: 1
Job description:
The Cancer Genomics lab, led by Ana Vivancos, seeks a post-doctoral candidate to work in the characterization of the molecular processes underlying tumor ctDNA shedding in blood.
In recent years, liquid biopsy has been proved as a viable alternative to the analysis of traditional tissue biopsy samples. Liquid biopsy arises as a minimally invasive and real-time assessment of the tumor heterogeneity and treatment response, particularly useful when tumor biopsy is inadequate or inexistent. Different components can be isolated from body fluids and used in liquid biopsy such as circulating tumor cells (CTCs) or extracellular vesicles (EVs) but circulating tumor DNA (ctDNA) is the biomarker with more diagnostic and prognostic potential (4).
Cell-free DNA (cfDNA) are fragments of DNA released into the bloodstream which originate mainly from the apoptosis of hematopoietic cells. In cancer patients, the concentration of cfDNA is increased as tumor-specific circulating DNA is present, ctDNA (5).
How ctDNA is released into the main bloodstream remains unclear. Many theories are under discussion; cancer cells can undergo cell death by apoptosis or necrosis, or actively shed via EVs (mainly exosomes) and protein complexes (6). cfDNA is cleared from the circulation via degradation to mononucleosomes by circulating enzymes (such as DNase I, plasma factor VII–activating protease (FSAP) and factor H); fragment size traces of cfDNA show a 10bp ladder pattern caused by continual DNA fragmentation in the regions of DNA not protected by histones. Surprisingly, ctDNA molecules are shorter than cfDNA in plasma, although the cause of this shortening is not clear; one of the hypothesis is the cancer-related hypomethylation of DNA, that is more accessible to cleavage by nucleases (7). Moreover, long cfDNA fragments (>1000bp) have been observed that may be released into the circulation in association with exosomes or via necrosis (5).
The amount and fraction of ctDNA at any given time is the result of an equilibrium between its release and clearance of cfDNA in the bloodstream and in organs, such as liver, spleen and kidney. The liver is the main organ for nucleosome clearance: 71.0% to 84.7% of the nucleosomes are removed from the circulation within 10 min. Kupffer cells in the liver and macrophages in the spleen are responsible for trapping and clearing DNA and nucleosomes (1).
The estimated half-life of ctDNA ranges from minutes to 1-2 hours (8) and is associated with factors such as encapsulation in vesicles or association with protein complexes, tumor type and treatment. The clearance of cfDNA also depends on the phisiological state of the patients and associated factors such as surgery, sepsis or inflamation (1). The exact mechanisms of cfDNA accumulation remain obscure, but it can be speculated that an excess of dying cells could overload the clearance system and cell content is released into the medium.
So, although certain tumor characteristics may be broadly associated with ctDNA levels, there are many other host factors that can affect this equilibrium. The goal of the project is to unveil and explain the interplay of the different processes that interplay in the shedding process.
References
(1) Kustanovich, A., Schwartz, R., Peretz, T. & Grinshpun, A. Life and death of circulating cell-free DNA. Cancer Biol. Ther. 20, (2019).
(2) Paweletz, C. P., Lau, C. J. & Oxnard, G. R. Does Testing Error Underlie Liquid Biopsy Discordance? https://doi.org/10.1200/PO.18.00408 1–3 (2019). doi:10.1200/PO.18.00408
(3) Vivancos A, Tabernero J. Circulating tumor DNA as a novel prognosti indicator. Nat Med. 2022 Nov;28(11):2255-2256. doi: 10.1038/s41591-022-02068-8. PMID: 36357679.
(4) Alix-Panabières C, Pantel K. Liquid Biopsy: From Discovery to Clinical Application. Cancer Discov. 2021 Apr;11(4):858-873. doi: 10.1158/2159-8290.CD-20-1311. PMID: 33811121.
(5) Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017 Apr;17(4):223-238. doi: 10.1038/nrc.2017.7. Epub 2017 Feb 24. PMID: 28233803.
(6) Grabuschnig S, Bronkhorst AJ, Holdenrieder S, Rosales Rodriguez I, Schliep KP, Schwendenwein D, Ungerer V, Sensen CW. Putative Origins of Cell-Free DNA in Humans: A Review of Active and Passive Nucleic Acid Release Mechanisms. Int J Mol Sci. 2020 Oct 29;21(21):8062. doi: 10.3390/ijms21218062. PMID: 33137955; PMCID: PMC7662960.
(7) Angeles AK, Janke F, Bauer S, Christopoulos P, Riediger AL, Sültmann H. Liquid Biopsies beyond Mutation Calling: Genomic and Epigenomic Features of Cell-Free DNA in Cancer. Cancers (Basel). 2021 Nov 10;13(22):5615. doi: 10.3390/cancers13225615. PMID: 34830770; PMCID: PMC8616179.
(8) Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008 Sep;14(9):985-90. doi: 10.1038/nm.1789. Epub 2007 Jul 31. PMID: 18670422; PMCID: PMC2820391.
(9) Bettegowda, C. et al. Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Sci. Transl. Med. 6, 224ra24 (2014).
(10) Serrano, C. et al. Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors. BMC Cancer 20, 1–12 (2020).
Requirements:
- PhD in Computational Oncology, Bioinformatics, Biology, Biochemistry, Biomedicine, Bioengineering, Molecular Biology or related scientific area.
- At least one paper as first author.
- Experience/ knowledge in bioinformatics (R, Python) and cancer.
- Proficiency in English.
Additional information:
Knowledge of statistical modelling or machine learning will be considered a plus.
Salary conditions will be set according to experience and profile.
Application:
Candidates must submit a curriculum vitae and letter of intent via email: selecciorrhh@vhio.net, including the reference number in the subject line of your email.
About VHIO Cancer Genomics Lab:
The Cancer Genomics Lab provides cutting-edge applications in cancer genomics through state-of-the-art technologies and, importantly, the development of novel, fully validated tests. Our novel genomic tests provide an important added value to our activity, enabling routine patient testing in the clinical research setting (Prescreening Program) as well as in translational research.
VHIO’s Prescreening Program is a transversal program, nucleated around the activity of two VHIO groups – the Molecular Oncology (led by Paolo Nuciforo) and Cancer Genomics labs, performing routine molecular profiling in over 1500 patients per year. Patients included in the program are candidates for enrollment in Phase I clinical trials carried out at the Research Unit for Molecular Therapy of Cancer (UITM) – “la Caixa”, led by Elena Garralda. Patients’ suitability for inclusion in any given clinical trial is decided taking into account their respective genomic or pathologic profile.
The Cancer Genomics Lab has developed and implemented several tests during the last 10 years that have been in use in the Prescreening Program routine. Tests for DNA profiling in tissue are NGS-based: an Amplicon-seq hotspot panel to sequence 67 genes (developed back in 2012) and a custom 435-gene hybrid capture panel (VHIO-300, developed in 2018), and an nCounter (Nanostring) panel for RNA gene fusion detection (with the capacity of detecting over 100 recurrent gene fusions) and perform gene expression profiling. As a reflection of our dedication to excellence and quality in the services we provide, both NGS-DNA based tests have been accredited according to the UNE-EN ISO 15189 quality system, that specifies requirements for
quality and competence in medical laboratories. In recognition to our track, VHIO-300’s UNE-EN ISO 15189 accreditation was awarded in its flexible version, allowing us to include new analytes directly in the accredited test (following a standard operating procedure).
In 2021, we initiated the technical transfer of the Food and Drug Administration (FDA)-approved Guardant360® CDx liquid biopsy test for comprehensive genomic profiling. VHIO es the first cancer research center in Europe to have a laboratory equipped with this cutting-edge platform.
About VHIO:
Under the leadership of Josep Tabernero, the Vall d’Hebron Institute of Oncology (VHIO), has established itself as a comprehensive cancer center of proven excellence internationally. It is also thanks to VHIO’s optimal organizational structure based on a purely multidisciplinary and translational model that VHIO talents continue to anticipate and tackle the many unresolved questions in combatting this multifaceted and heterogeneous disease.
Located within the Vall d’Hebron Barcelona Hospital Campus, our researchers closely collaborate and interact with Vall d’Hebron physician-scientists. Translational science and clinical research are therefore tightly connected which promotes superb interaction and teamwork which, in turn, accelerates the bench-bedside-bed cycle of knowledge. This privileged environment affords VHIO direct access to patients as well as the entire spectrum of oncology professionals who care for them, and a second-to-none appreciation of how cancer science can translate into more powerful, targeted treatments and better practice for the care of patients.
VHIO’s pioneering model and programs, coupled with its belief in combining strengths through cross-border collaborations, continue to spur advances in reversing cancer resistance, halting metastatic spread, and more effectively treating even the most undruggable tumor types.
VHIO’s translation toward precision oncology: https://www.vhio.net
Vall d’Hebron Institute Oncology (VHIO) endorses the Requirements and Principles of the European Charter for Researchers, the Code of Conduct for the Recruitment of Researchers promoted by the European Commission and follows Equal Opportunities policies.
On 10th April 2018 VHIO was awarded the “HR Excellence in Research” logo. Our Institute was consequently granted permission to use the HR Excellence in Research Award logo as demonstration of its stimulating and favourable work environment in line with the Charter & Code.
