VHIO launches a Master Internship Programme for excellent and motivated students that wish to do the Master Thesis @ VHIO. Apply now to boost your scientific career in a Translational Research Center of Excellence.
In this call, we do offer 6 internships for international life sciences Master students. Deadline 30th of November 2022
Decide which Masters Project fits better your research interests
and APPLY through our online application portal
Candidates should fulfil the following eligibility criteria at the time of the call deadline:
- Master students in Life Sciences or related subjects (e.g., Bioinformatics, Mathematics, Medicine, Biochemistry, Chemistry, Physics, etc) with an excellent academic record and a strong commitment to scientific research
- Enrolled in the Master Programme of their choice. Candidates may not have received a master’s degree at the time of the Internship
- High level of English
- Availability to do a student placement/internship agreement through the correspondent University
Selected candidates will receive a monthly stipend of 650€ for five months during the first semester of 2023 ( Jan/Feb – Jun/Jul). The fellows will sign an agreement between the University and VHIO which will include insurance coverage.
All fellows will have access to an exceptional scientific environment, including outstanding equipment and facilities, together with a wide range of training opportunities, including access to seminars and some training workshops.
Interested candidates should apply via the VHIO online form including the following information:
- Personal and academic data, indicating the master in which the applicant is enrolled
- BSc certified academic record
- Letter of motivation, highlighting your interest towards a specific Masters project
- Brief summary of previous research experience (if any)
- Applicants should select up to two research groups/projects
Eligible applications will be assessed based on the information provided in the application form by an internal evaluation committee. Short-listed candidates might be invited for an interview with the group leader who has shown interest in the applicant.
- Call opening: 26 October 2022
- Call deadline: 30 November 2022
- Selection process: Early December
- Incorporation: As of mid-January 2023
PROJECT DESCRIPTION
Towards next-generation immunotherapy of cholangiocarcinoma | Tian Tian, MD. PhD
Cholangiocarcinomas (CCAs) are the second-most common hepatobiliary malignancy and remain incurable (5-year survival rate, 7–20%). CCA is a highly heterogeneous tumor, and its complex cellular composition could explain its resistance to treatment and poor prognosis. How CCA cells relate to the tumor microenvironment (TME) and the immune system is largely unknown. Recurrent somatic mutations are found in the majority of patients with intrahepatic CCA. Nonetheless, the functional impacts of these mutations on CCA cells and tumor microenvironments are still unclear. Preliminary data obtained in our laboratory now suggest that the expression of immune-related genes is downregulated in a subset of CCA patients with a specific mutational landscape. To further characterize this phenotype, functional studies will be performed using our established CCA patient-derived xenograft (CCA_PDX) ex vivo and in vivo. Taken together, these data will help to develop new CCA immunotherapy strategies.
Immunosenescence and cancer: assessing the role of immune aging in cancer onset | Mate Maus, PhD
Aging is the best predictor of cancer, however, which age-associated processes account for this association remains unclear. We propose that aging of the immune system could be a major cause of rising cancer incidence with age. This master´s thesis will test if age-associated changes in the lymphoid organs and in circulating immune cells are predictive of cancer. The student will analyze lymphoid organs and T lymphocytes from young and old mice by histology, flow-cytometry, and by epigenomics. A background in immunology, oncology and some bioinformatics are an advantage. This work will lay the groundwork for a larger project entailing a PhD thesis, in which the successful candidate will (1.) develop diagnostic tools that measure immune aging to thereby stratify cancer patients, and (2.) find novel immunotherapeutic interventions that target immune aging for the treatment of cancer.
In-silico discovery of drug response differences between primary and metastatic cell lines | José Antonio Seoane, PhD
The molecular profile of metastatic tumors is not reflecting the patterns observed on the primary in many cases, however in drug discovery process using cell line models, both primary and metastatic cell lines are used indistinctly. In this project we will computationally analyze the differences between primary and metastatic cell lines according to their response to drugs using data from CCLE and drug response databases and identify drugs that would be more effective in metastatic patients.
STEAP1 as a precision medicine biomarker for novel immunotherapies | Joaquin Mateo, M.D. PhD
Immunotherapy has so far failed to make an impact in prostate cancer care. Our clinical team is pursuing clinical trials with a novel bispecific CD3-STEAP1 antibody; STEAP1 is a cell-surface antigen highly expressed in prostate cancer. In this project, the student will develop a non-invasive liquid biopsy assay to identify patients with highest levels of STEAP1 expression who could benefit from this drug. We will leverage plasma from in vivo xenograft prostate cancer models to optimize an ELISA assay for measuring STEAP1 expression in circulating extracellular vesicles, to then correlate them with STEAP1 tumor expression by IHC and RNAseq. Next, we will pursue validation of these data in plasma samples from metastatic prostate cancer patients, correlating STEAP1 EV expression with IHC and RNAseq data from the contemporary tumor biopsies of the same patients.
Generation and validation of novel p95HER2 CAR-T cells against breast cancer | Joaquín Arribas López, MD. PhD
T lymphocyte redirection against tumor-associated or tumor-specific antigens via bispecific T-cells engagers (BiTEs) or chimeric antigen receptors (CARs) is a successful therapeutic strategy against certain hematologic malignancies. Conversely, these approaches face several difficulties against solid tumors. For instance, the direction of BiTEs and CARs against tumor-associated antigens, which are also present at low levels in normal tissues, has caused severe adverse effects. We addressed this issue by targeting a truncated form of HER2 (p95HER2), a bonafide tumor-specific antigen expressed in around 40% of HER2-amplified tumors. The student joining this project will use different in vitro molecular biology techniques to improve the efficacy of our p95HER2 CAR-T cells by testing armoring approaches that should improve our CAR-T antitumor potential in p95HER2-positive breast tumors.
Validation and characterization of vulnerabilities to overcome immunotherapy resistance: a CRISPR/drug screening approach | Enrique Arenas Lahuerta, PhD | Joaquín Arribas López, M.D PhD
Immunotherapy has raised high expectations to treat virtually every cancer, but resistance still arises. Using T-cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) directed against HER2, we have recently shown that disrupting the tumoral intrinsic interferon-gamma (IFN-γ) signaling confers resistance to tumoral cells to being eliminated by active T lymphocytes. Our current efforts focus on overcoming this resistance through the IFN-γ signaling restimulation. To this aim, we performed a genome-wide CRISPR and a drug screening in our resistant model to identify the pathway’s critical regulators and possible vulnerabilities. In this master thesis, the student will validate the candidate genes and drugs found on the screening to overcome immunotherapy resistance, using cytotoxic assays and gain- and loss-of-function approaches.
Identification of the best scRNAseq immunological annotation tool for incorporation into our Nextflow pipeline | Lara Nonell, PhD
Single-cell RNA sequencing (scRNAseq) techniques are powerful tools to gain insights into cellular heterogeneity in tissues and to identify previously unknown cell types. This has special relevance in the fields of immunology and immunotherapy. Cell type annotation, using reference sets, is a crucial step in the analysis of scRNAseq data that conditions subsequent analyses (Luecken et al., 2019). However, there is a lack of consensus on which is the best approach.
Nextflow is a workflow management system that enables scalable and reproducible scientific workflows using software containers. VHIO’s computational facilities operate with Slurm, Docker and Nextflow to optimize resources and guarantee reproducibility of bioinformatic analyses.
The main objective of this master thesis is to compare current annotation tools using several real scRNAseq data sets in the immunology field and to identify which is the most accurate tool so it can be subsequently incorporated into our Nextflow pipeline.
Detection Of Homologous Recombination Deficiency From Different Assays in Advanced Prostate Cancer Biopsies | Joaquín Mateo, M.D. PhD | Lara Nonell, PhD
Metastatic prostate cancer is enriched for DNA damage repair (DDR) alterations that can guide precision medicine indications such as the novel poly(ADP-ribose) polymerase inhibitors (PARPi) therapy.
BRCA1/2 genomic alterations are the most common events leading to homologous recombination deficiency (HRD) in prostate cancer. HRD tumors are characterized by genomic signatures, which are usually measured by whole-exome or whole-genome assays. However, certain features of HRD, such as long-scale transitions (LST) can be computed from low-pass WGS (shallow WGS). We have completed WES and targeted sequencing analysis for a cohort of metastatic prostate cancer biopsies for which we have also performed in parallel shallow WGS from the same input DNA. In this project, the candidate will implement bioinformatic tools to study and compare the robustness of parameters relevant for HRD signatures from same-patient shallow WGS and WES. This is a joint project between VHIO Bioinformatics Unit and Prostate Cancer Research Lab.
Functional blood assay for uncovering pathogenicity of variants of unknown clinical significance in BRCA1/2 and PALB2 hereditary cancer genes | Judith Balmaña, M.D. PhD | Sara Gutiérrez-Enríquez, PhD
Identification of causative variants in genes with a clinical applicability is important for determining cancer risk in at-risk relatives, guiding the enrolment of carriers in cancer surveillance and prevention programs, and benefiting of personalized cancer therapies. With the deployment of massively parallel sequencing technologies, the identification of variants of uncertain significance (VUS) in cancer predisposing genes is substantially expanding. Experimental analyses are strongly indicated to assess the impact of a genetic variant on a specific function as well as for aiding clinical variant classification. We propose to implement RAD51 foci detection (a biomarker of the status of homologous recombination DNA repair) as a feasible method for variant functional characterization using blood cells derived from BRCA1/2 and PALB2 VUS carriers.
Using MYC inhibition to overcome immunotherapy resistance in Kras-driven NSCLC with diverse mutational profiles | Laura Soucek, PhD | Sílvia Casacuberta, PhD
In Non-small-cell lung cancer (NSCLC), KRAS is the most frequently mutated oncogene, conferring poor prognosis. To overcome the downsides that current therapies have, we propose a revolutionary strategy based on the inhibition of MYC, a transcription factor downstream of KRAS, which is a central molecule that drives multiple aspects of tumor progression and immune evasion, using a MYC dominant negative called Omomyc.
In KRAS-mutant tumors, concomitant mutations in tumor suppressor genes negatively affect the response towards treatments and influence the tumor microenvironment. In this regard, we aim to determine the effect of MYC inhibition by Omomyc in these different mutational profiles using PDX-derived organoids and study the differential expression of immune-regulating molecules after treatment. In addition, we will set up humanized mouse models to study the therapeutic effect, and also study how these concomitant mutations influence the tumor immune microenvironment in syngeneic mouse models with the same mutational profiles.
Improving immunotherapy in lymphoid malignancies | Marta Crespo, PhD | Francesc BOSCH. M.D. PhD
Chronic lymphocytic leukemia (CLL) is mainly diagnosed at early asymptomatic stages while in about half of the patients, the disease will eventually progress and treatment will be needed. The mechanisms underlying progression are not fully elucidated and the identification of patients with higher probability of short time to progression is still a challenge. Preliminar longitudinal studies carried out by our group indicate that progression in CLL is characterized by a progressive dysfunction of the immune system. The deletion of 13q14, the most common genetic alteration in CLL, induces the development of CLL in animal models with relatively low penetrance, which could be explained by control by T lymphocytes.
Based on these data our goal is to decode the immunological mechanisms involved in CLL progresion and to transfer this information into a better prognostication and treatment selection.
We will study genome-wide expression changes in both CLL and immune system cells by means of RNAseq and multiparametic spectral flow cytometry.We will also study immunological characteristics in mice with 13q14 deletion according to the development of CLL and will test immunomodulatory therapies that can potentially impede CLL progression. Finally, the absolute increase in immune dysfunction will be computed and combined with other prognostic factors, to build an algorythim to predict time to progression.
