Research Fellow in Brain Vascular Biology and Brain Cancer Biology

LONDON’S GLOBAL UNIVERSITY

Job Description

Research Fellow in Brain Vascular Biology and Brain Cancer Biology

Department: Research Department of Oncology

Reports to

Dr Thomas Wälchli, Associate Professor/Principal Clinical Research Fellow and Honorary Consultant Neurosurgeon The UCL Cancer Institute The UCL Cancer Institute is a £40 million investment in central London based at University College London (UCL), one of the world’s top universities and a founding member of the Francis Crick Institute. The Institute draws together over 400 scientists working together to develop world-class basic and translational cancer research.

The 2007 opening of the UCL Cancer Institute in the Paul O'Gorman Building heralded a new era in cancer research and medicine at UCL. The Institute is consolidating cancer research across the campus in a vibrant international research environment, and is the hub for cancer research at University College London.

The Institute draws together over talented who are to

Grade: 7

Salary range: £43,981-£54,019 per annum inclusive of London

Allowance

Location: Paul O’Gorman Building scientists working together translate research discoveries into developing better, more effective treatments to improve outcomes for cancer patients. In particular, it fosters links between basic cancer researchers across Biomedicine , and with the clinical activities of our four partner Hospital trusts, known as UCL Partners: University College London Hospital NHS Foundation Trust, Great Ormond Street Hospital for Children NHS Trust, the Page of

Royal Free Hampstead NHS Trust, and Moorfields Eye Hospital NHS Foundation Trust, as well as the London School of Pharmacy and Cancer Research UK.

The Institute has greater clinical links than any comparable centre in the UK, creating a unique opportunity for significant impact on the delivery of groundbreaking basic and translational science as well as clinical service to cancer patients.

The Cancer Institute includes the Cancer Research UK and UCL Cancer Trials Centre largest cancer trials centres in the UK conducting multi-centre national and international phase III trials, feasibility studies and early phase I and II studies.

Also embedded within the UCL Cancer Institute, the support cancer research within UCL and is a major catalyst in the success of UCL in integrating translational and clinical cancer research with excellent basic programmes that reflect the depth and breadth of research expertise that include BSc Cancer Biomedicine, iBSc Oncology, MSc Cancer and PhD studies.

Further Information about the UCL Cancer Institute can be found on our website The role will be available for one year in the first instance with the possibility of extension.

Appointment at Grade 7 is dependent upon having been awarded a PhD; if this is not the case, initial appointment will be at Research Assistant Grade 6B, with payment at Grade 7 being backdated to the date of final submission of the PhD thesis.

Applications should include a CV and a Cover Letter: essential and desirable criteria in the Person Specification part of the Job Description. (By including a Cover Letter, you can leave blank the 'Why you have applied for this role' field in the application form, which is limited in the number of characters it will allow.) Main purpose and aims of the job The Group of CNS Angiogenesis and Neurovascular Link / Brain Vasculature and Perivascular Niche headed by neurosurgeon-neuroscientist Associate Professor of the University College London (UCL) Cancer Institute College London (UCL). The Cancer Institute is part of the Faculty of Medical Sciences within the School of Lifeand Medical Sciences of University College London (London, UK). The overarching vision of the research of Associate Professor Dr Thomas Wälchli, MD-PhD, FMH neurosurgery vasculature is regulated during brain development, in the adult healthy brain, and in various vascular-dependent brain diseases such as brain tumours and brain vascular malformations.

Accordingly, the Group of Brain Vasculature and Perivascular Niche development of blood vessels (angiogenesis) in the the neurovascular unit/perivascular niche, and on brain disease: The main aims are: i) to understand the cellular and molecular underpinnings that govern the growth of the developing, adult, and diseased human brain vasculature at single-cell resolution, ii) to uncover the singlecell transcriptomic, genomic and epigenomic landscapes and spatial biology of the developing, adult and diseased human brain vasculature, iii) to elucidate how which is one of the CRUK-UCL Centre provides essential infrastructure to science. Furthermore, the Institute offers educational https://www.ucl.ac.uk/cancer/ In the Cover Letter please provide evidence of the Dr Thomas Wälchli is one of the laboratories in the Department of Oncology of the University is to understand how the brain focuses on vascular growth and the brain, including endothelial cells and perivascular cells of vascular heterogeneity in development, health and developmental programs regulate vascular growth/angiogenesis in the human brain tumour vasculature (patho-fetal axis / onco-fetal axis), iv) to unravel the Page of

onco-fetal programs of vascular growth/angiogenesis and immunosuppression/immunomodulation, and v) to translate these fundamental insights about the onco-fetal axis in the human brain (tumour) vasculature into clinical settings with the ultimate goal to identify novel therapeutic strategies for human brain tumours (and for other vascular-dependent diseases such as human brain vascular malformations).

To tackle these fundamental challenges regarding the biology of the human brain vasculature in development, adulthood and disease, the group uses a variety of state-of-the-art technologies, including single-cell and spatial multi-omics, imaging mass cytometry, advanced imaging of human and mouse tissues, and innovative somatic mouse models. The focus of the team is on the most aggressive human brain tumours, notably primary brain tumours such as glial brain tumours (lower-grade gliomas, and the highly aggressive glioblastoma (GBMs)) as well as on secondary brain tumours such as brain metastases. The ultimate goal is to develop novel and conceptually different treatment strategies. Specific areas of focus are the developmental mechanisms (pathofetal programs or onco-fetal programs) driving vascular growth in the human fetal brain and in human brain tumours, and how they are linked to immunosuppressive signals in the perivascular niche.

The successful candidate is be expected to be a driving force of these highly novel, original and competitive projects, to produce independent and original research in this area, to develop and apply new concepts and to have a creative approach to problem solving.

Background of the project

The Central Nervous System (CNS) critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease, and cerebrovascular disease is a leading cause of death worldwide (Wälchli et al., Nature, 2024 (

; https://www.nature.com/articles/d41586-024-02284-x), et al., Nat Rev

, (https://www.nature.com/articles/s41583-023-00684-y), et al., , (https://pubmed.ncbi.nlm.nih.gov/26182414/)). Angiogenesis —

— active during embryonic and postnatal brain development (Wälchli et al., (https://www.pnas.org/doi/abs/10.1073/pnas.1216203110), et al., Nat

, (https://www.nature.com/articles/nprot.2015.002); et al., J

Flow

, (https://pubmed.ncbi.nlm.nih.gov/27927704/); et al., Nat

, (https://www.nature.com/articles/s41596-021-00587-1); Wälchli et al., (https://pubmed.ncbi.nlm.nih.gov/35196110/)), enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as and malformations (Schwab et al…Wälchli, JCI Insight, 2023 ( al., Nature, 2024 (

; https://www.nature.com/articles/d41586-024-02284-x), et al., Nat Rev

, (https://www.nature.com/articles/s41583-023-00684-y cellular and molecular mechanisms driving angiogenesis in pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood.. The mouse and human brain vasculature is established via an interplay of general and CNSspecific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours (Wälchli et al., Neuron, 2015 (https://pubmed.ncbi.nlm.nih.gov/26182414/ Neurosci, 2023 (https://www.nature.com/articles/s41583-023-00684-y that are reactivated in vascular-dependent diseases et al., Nat Rev

, (https://www.nature.com/articles/s41583-023-00684-y); et al., , (https://www.nature.com/articles/s41586-024-07493-y;

)).

https://www.nature.com/articles/s41586-024-07493-y

Wälchli

Neurosci 2023

Wälchli

Neuron 2015 the formation of new blood vessels is highly

Proc Natl Acad Sci USA, 2013

Wälchli

Protoc 2015

Wälchli Cereb Blood

Metab 2017

Wälchli

Protoc 2021

Arterioscler Thromb Vasc Biol, 2022 brain tumours brain vascular https://insight.jci.org/articles/view/143071); Wälchli et https://www.nature.com/articles/s41586-024-07493-y

Wälchli

Neurosci 2023

)). Despite major advances in the understanding of the peripheral tissues, developmental signalling

)); Wälchli et al., Nat Rev

)), and key molecular signalling pathways (Wälchli

Neurosci 2023

Wälchli

Nature 2024 https://www.nature.com/articles/d41586-024-02284-x

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Conventional, single target approaches to modulate pathological human CNS vasculature (e.g. in brain tumours) have failed to improve outcomes and integrate standard clinical practice (Wälchli et al., (https://www.nature.com/articles/s41583-023-00684-y)).

have the heterogeneity and spatial architecture of the human brain vasculature transcriptome/epigenome at the single cell (sc) level, nor the potential reactivation of developmental programs in cancer, a phenomenon referred to as the onco-fetal axis. We hypothesize that onco-fetal programs contribute to this sc-heterogeneity and are key regulators of vascular growth in brain tumours. We address the human brain (tumor) vasculature in a systems biology approach utilising sc-multi-omics and CRISPR-Cas multiplexing mouse models to bridge the currently existing translational gap between human and mouse glioma biology. Our work aims to pave the way for therapies targeting onco-fetal candidates in the human brain tumour vasculature.

We recently performed scRNA-seq on approximately 600,000 freshly isolated ECs and PVCs from 47 fetuses and adult patients (Wälchli et al., Nature, 2024 (

; associated Research Briefing in Nature https://www.nature.com/articles/d41586-024-02284-x; Research Highlight in Nature Neuroscience https://www.nature.com/articles/s41593-024-01759-4 News & Views in Nature Reviews Cardiology https://www.nature.com/articles/s41569-024-01079-x unprecedented insight into EC and PVC heterogeneity and functional specialization of the human brain vasculature in development, health and disease at the single-cell level revealed the top differentially regulated pathways in both fetal and pathological brain ECs (including those in both low-grade and high-grade gliomas) as compared with healthy adult brain ECs. This single-cell atlas further unravelled that these reactivated pathways belong to five canonical groups, namely angiogenesis-related pathways, development and NVL molecules, cell – cell and cell – ECM interactions, immune-related processes and metabolism.

In development, adulthood, and disease, and immunosuppression/immunomodulation are tightly linked to allow for undisturbed tissue (i.e. embryonic or tumor tissue) growth (Huinen et al., https://www.nature.com/articles/s41571-021-00496-y, et al., Sci

, https://www.science.org/doi/10.1126/sciimmunol.abm6388?url_ver=Z39.882003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed). This angiogenesis/vascular growth and immunosuppression/immunomodulation is of fundamental relevance to generate immunologically silent conditions allowing immunosuppressive tumor microenvironment, the tumor vasculature reactivates embryonic/onco-fetal vascular gene programs that convey angiogenesis/vascular growth and immunosuppression/immunomodulation during embroygenesis/fetogenesis (Huijbers et al., Sci

, (https://www.science.org/doi/10.1126/sciimmunol.abm6388?url_ver=Z39.882003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed)).

a of Nat Rev Neurosci, 2023

These strategies neither addressed https://www.nature.com/articles/s41586-024-07493-y associated

; associated

)). This vascular growth/angiogenesis

Nat Rev Clin Oncol 2021, Huijbers

Immunol 2022, onco-fetal program linking to escape from immunity Accordingly, to create an Immunol

2022

Accordingly, better understanding these onco-fetal programs linking vascular growth/angiogenesis and immunosuppression is not only crucial for fundamental insights into vascular growth and endothelial-immune interactions , but may also allow the development of novel therapeutic strategies combining anti-angiogenic- and immunotherapies for various cancers including human brain tumours.

As London’s Global University, we know diversity fosters creativity and innovation. We are committed to equality of opportunity, to being fair and inclusive, and to being a place where all belong. We therefore particularly encourage applications from candidates who are likely to be underrepresented in UCL’s workforce. These include people from Black, Asian and minority ethnic backgrounds, disabled people, LGBTQI+ people, and women.

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Key requirements – Your Profile

We are exclusively looking for outstanding and highly motivated candidates.

To tackle the above-mentioned high risk-high potential projects, candidates should demonstrate overwhelming enthusiasm for single-cell genomics, neuroscience, vascular biology, developmental biology, and cancer/tumor biology. A central component of the project will be the analysis, evaluation and interpretation of largescale molecular (single-cell and spatial multi-omics) data using the latest bioinformatics/single-cell and spatial multi-omics tools and strategies. Therefore, excellent training, experience, knowledge, and enthusiasm in/for molecular- and cell biology, and single-cell and spatial multi-omics and computational biology/bioinformatics and biostatistics are required.

Moreover, the candidate should be highly motivated and display a flexibility with regard to experimental (combination of various in vivo and in vitro experiments of human and mouse tissues) and organizational (the candidate will work at the University College London, in close collaboration with the Toronto Western Hospital, University Health Network and the University of Toronto) aspects. Therefore, we feel that only very dedicated, motivated, and talented candidates will be able to successfully work on the above-described, highly novel, original, translational and competitive projects with the potential to significantly enhance our knowledge on the biology of the human brain vasculature in development, adulthood, and disease.

Finally, the candidate should have the ability and self-motivation to work both independently and as a team player and should demonstrate good communication skills.

The successful candidates

• Have a PhD in bioinformatics/single-cell genomics/computer science (AI), neuroscience, vascular biology, developmental biology, cancer biology, immunology, biology/biomedicine, pharmacy, biomedical engineering, or related fields with ample research experience
• Have strong skills in working in the fields of bioinformatics/single-cell genomics and/or spatial multiomics, neuroscience, vascular biology, developmental biology, cancer biology and immunology and/or experience in biotech, intellectual protection, etc. are an extra-added value
• Have a proven publication record with at least one first author publication in peer-reviewed international journals.
• Have experience in: (i) integrating single-cell and spatial multi-omics; (ii) computational programming in R, Python (and other common computer languages); (iii) competence/interest in analysing and integrating complex single-cell and spatial multi-omics- and clinical datasets are essential.
• will be an ambitious researcher, motivated to apply his/her skills to diverse (medical) research projects and enjoy working in a collaborative, dynamic, vibrant and fast-paced team environment.
• Have excellent organizational and supervisory skills, you can work in a team as well as independently.
• Have a strong ability to multi-task, to meet timelines, to work accurately; you are stress-resistant.
• Have outstanding written and verbal communication skills in English.
• Are able to identify priorities, and to find solutions for complex or difficult tasks.
• Have excellent organizational and record-keeping skills
• Have experience in presenting complex scientific concepts and content both in writing and verbally
• Have a strong commitment to enhance our fundamental understanding of human brain vascular biology and to improving outcomes for brain tumor patients
• Demonstrate excellent collaborative interpersonal skills with an ability to work co-operatively in a highly interand multidisciplinary setting.

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• Have the ability to assist other members of the team, supervise MSc and PhD students and collaborate with other research groups.

For informal inquiries please contact Associate Dr by thomas.waelchli2@uzh.ch; t.waelchli@ucl.ac.uk; kaerefrei@bluewin.ch to all three e-mail addresses).

Duties and responsibilities

• Contribute in all phases of the project lifecycle, from study design to publication.
• Plan, develop and carry out original research.
• To conduct data analysis ensuring its validity and reliability of data at all times.
• To maintain accurate and complete records of all findings.
• To run analyses and tests using specified and agreed techniques and models.
• To help with the smooth running, organization of the laboratory and ensuring that GLP is observed in all procedures directly related to the research project.
• To prioritise tasks within agreed work schedules.
• Keep abreast of relevant literature and methodology developments relevant to the field.
• Communicate with the Group Leader and other group members on a regular basis to discuss projects updates.
• Attend weekly laboratory meetings and interact collaboratively with other scientific staff .
• Attend appropriate scientific seminars, meetings, conferences and relevant training opportunities.
• Participate in the activities of the group and department, contributing scientific ideas and innovative solutions.
• To develop contacts and research collaborations within the institute and research fields
• To assist with other various tasks related to lab management, if and when the need arises.
• Provide guidance as required to support staff and any students who may be assisting with research.
• To help prepare and submit grants to appropriate funders.
• To maintain awareness of health and safety regulations; to make sure all risk assessments are up to-date and to ensure that all codes of practice are being followed.
• As duties and responsibilities change, the job will be and in consultation with the post holder.
• The postholder will carry out any other duties as are within the scope, spirit and purpose of the job as requested by the line manager.
• The postholder will actively follow UCL policies including Equal Opportunities and Race Equality policies.
• The postholder will maintain an awareness and of Fire and & Regulations.

Professor

Thomas Wälchli email: (please send applications simultaneously description reviewed amended observation

Health Safety

• To be aware of and act upon: -Disciplinary procedure and Disciplinary rules -Grievance procedure

-Section 7 and 8 of the Health and Safety at Work Act

-Departmental Fire Guidelines

-Equal Opportunities Policy

• To comply with the Health & Safety regulations of the department.

University College London has adopted an equal opportunities policy and specific regard should be taken of its content in relation to the treatment of employees or potential employees.

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This job description is not meant to be restrictive or exhaustive, and duties may change in response to changing circumstances. These will be discussed with the postholder.

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Person specification

Essential Criteria

Qualifications, experience and knowledge

PhD in a relevant subject.

BSc in relevant subject (First or Upper Second class honours) Extensive expertise in bioinformatics/single-cell genomics and/or spatial multiomics Extensive expertise experience in: (i) integrating single-cell and spatial multiomics; (ii) computational programming in R, Python (and other common computer languages); (iii) competence/interest in analysing and integrating complex singlecell and spatial multi-omics- and clinical datasets are essential.

Proven track record of scientific publication and conference presentations, commensurate with the career stage Extensive expertise in molecular biology techniques Experience in image processing and image analysis

Skills and abilities

Ability to work independently and under own initiative, self-starter Ability to design research studies and learn new skills Experience in supervision (PhD and/or MSc students) Excellent communication skills Analytical and critical thinking Creativity in problem solving, a flexible approach to tasks and adaptability

Personal attributes

Excellent collaborative interpersonal skills with an ability to work co-operatively in a multidisciplinary setting.

Highly-motivated, enthusiastic and proactive Commitment to UCL’s policy of equal opportunity and the ability to work Application Application Application Application Application harmoniously with colleagues and students of all cultures and backgrounds.

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Desirable Criteria

## Qualifications, experience and knowledge

Extensive expertise in primary tissue culture Extensive expertise in histology and immunohistochemistry, Extensive experience with mouse models and in vivo methods Home office personal license modules 1-4 Experience in surgical techniques

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