Identifying biomarkers and therapeutic targets in primary breast angiosarcoma using iPSC-derived endothelial models

Dr Ralitsa Madsen (CRUK SI) & Prof Alex Toker (Harvard Medical School)

Funding: Sarcoma UK
Lab: Cell State Control of Oncogenic Signalling
Duration: 4 years, starting October 2026
Closing Date: 24 April 2026

 APPLY HERE

Please note, for your application to be considered, you must upload your CV and a completed document CRUK EDI Recruitment Form(107 KB) .

• We ask that you do not add your name or any Institution details to the CRUK EDI Recruitment Form

• Applications will be shortlisted initially based on the CRUK EDI Recruitment Form only. CVs will be used in further rounds of shortlisting to invite candidates to interview.

Background

Angiosarcomas are aggressive soft tissue tumours arising in the endothelial cells lining blood vessels. Primary angiosarcoma of the breast (PBA) is rare, representing 0.05% of all breast cancers and <5% of soft tissue sarcomas (Benton et al. 2025). Unlike secondary angiosarcomas, PBA lacks an association with radiation exposure or other risk factors. It affects relatively younger individuals, with a median age of onset of 40 years; rare cases of the disease in adolescent females have also been reported (Zhu et al. 2024). There is no established clinical management protocol for PBA, with aggressive treatment and ongoing surveillance considered the only options to prolong survival (Lee et al. 2023; Zhu et al. 2024). The accurate diagnosis of PBA represents a key challenge due to a deceptively benign appearance, often leading to delayed diagnosis or misdiagnosis as haemangioma, lymphangioma, hematoma or dysplasia (Zhu et al. 2024; An et al. 2024). There is thus a critical need for better diagnostic markers. Despite complete surgical excision, local recurrence and metastatic rates for PBA remain high due to its hematogenic route of spreading (Zhu et al. 2024; An et al. 2024), underscoring the additional unmet need for targeted and effective therapies. The prognosis of primary breast angiosarcoma is poor, with a 5-year survival rate of 46 % (Zhu et al. 2024; An et al. 2024).

Due to its rarity, the aetiology and pathogenic mechanisms of PBA remain poorly understood. As highlighted by the patient-partnered Angiosarcoma Project (Painter et al. 2020), PBA is also molecularly distinct within the angiosarcoma family and shows enrichment for activating mutations in both KDR and PIK3CA. KDR (kinase insert domain receptor), also known as vascular endothelial growth factor receptor 2 (VEGFR2), is a key mediator of angiogenesis and activates canonical growth-promoting pathways including phosphoinositide 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/RAS.  PIK3CA encodes the catalytic p110 subunit of the PI3Ka isoform and is one of the most frequently mutated oncogenes in carcinomas; in contrast, such alterations are rare across the wider sarcoma spectrum, underscoring the specificity of this genetic signal in PBA. Activating PIK3CA mutations are found in 50% of PBA cases; of these, 75% also harbour either a KDR mutation (T771R) or gene amplification. PIK3CA mutations in PBA are “non-hotspot”, i.e. not the commonly observed E542K/E545K/H1047R variants seen in carcinomas. Importantly, mosaic activating mutations in PIK3CA (hotspot and non-hotspot) are established drivers of rare but benign vascular malformations, either in isolation or as part of syndromic disorders¹. The observation that endothelial PIK3CA mutations alone are insufficient to trigger malignant transformation, combined with the frequent co-occurrence of PIK3CA-KDR alterations in PBA, suggests that this oncogenic pair may cooperate to direct tumour initiation, progression and therapy response. Dissecting how this driver-duo remodels endothelial signalling and drug sensitivities could reveal actionable biomarkers and therapeutic strategies for this lethal disease.

Research Question

Genomic studies of PBA have identified frequent co-occurring activating mutations in PIK3CA and KDR, suggesting a cooperative oncogenic programme; however, how these alterations reshape endothelial cell state, drive malignant transformation, and create therapeutic vulnerabilities remains unknown.

This Sarcoma UK PhD studentship will address this critical gap by establishing the first genetically defined human iPSC-derived endothelial models of PBA, alongside the first spatial molecular profiling of patient tissues. Integration across these experimental and human systems will enable identification of novel diagnostic biomarkers and therapeutic targets. Using inducible and precisely titrated expression systems, the student will model PIK3CA and KDR mutations alone and in combination within arterial and venous endothelial contexts. Combined with advanced lineage barcodes, these models will be used to define early transformation events, uncover actionable signalling dependencies, and evaluate targeted combination therapies using clinically relevant agents.

Skills/Techniques that will be gained

This studentship is designed to provide comprehensive, interdisciplinary training at the interface of stem cell biology, cancer research, and quantitative multi-omics, preparing the student for careers across academia, industry, and the third sector.

1. Precision disease modelling and genetic engineering

• Human iPSC culture and differentiation into arterial and venous endothelial lineages
• Transposon-based genetic engineering using inducible gene expression systems
• Advanced lineage barcoding as complementary approach

2. Advanced vascular and 3D model systems

• 2D and 3D endothelial culture systems,including flow-based (microfluidic) culture
• Quantitative assessment of endothelial dysfunction and transformation phenotypes

3. Molecular and phenotypic profiling

• High-content imaging and morphometric analysis of 2D and 3D culture systems
• Single-cell signalling analysis using mass cytometry (CyTOF)
• Quantitative proteomics (including IP-MS workflows)
• Spatial transcriptomics and multiplexed imaging on patient-derived tissue
• Cytokine/secretome profiling for biomarker discovery

4. Drug screening and preclinical therapeutic evaluation

• Design and execution of drug screening assays using clinically relevant compounds
• Evaluation of pathway dependencies and rational combination therapies

5. Computational and multi-omic data integration

• Integration of transcriptomic, proteomic, and imaging data
• Exposure to computational approaches for modelling cell state transitions

6. Clinical and international research exposure

• Interaction with clinician-scientist Prof. Robin Jones (Royal Marsden/ICR), providing direct insight into sarcoma biology and clinical translation
• Collaboration with Prof. Alex Toker (Beth Israel Deaconess Medical Center, Harvard Medical School)
• Participation in an international, multidisciplinary research network

7. Patient engagement and third-sector training (unique feature)

• Direct engagement with Sarcoma UK and its patient community throughout the project
• Regular reporting of research progress in accessible formats to patients and non-specialist audiences
• Involvement in patient-informed discussions shaping research priorities and interpretation
• Training in responsible communication of complex biomedical research.

This component provides a unique opportunity to develop skills highly valued in the third sector, including patient engagement, science communication, and impact-driven research design.

8. Reproducible, team-based science and project leadership

• Training in reproducible and traceable research practices
• Milestone-driven project planning and delivery
• Scientific communication across disciplines
• Experience working within a collaborative, team-science environment

For questions regarding the application process, PhD programme/studentships at the CRUK Scotland Institute or any other queries, please contact phdstudentships@crukscotlandinstitute.ac.uk.

Closing date: 24 April 2026

Applications are open to all individuals irrespective of nationality or country of residence.

 APPLY HERE

Please note, for your application to be considered, you must upload your CV and a completed document CRUK EDI Recruitment Form(107 KB) .

• We ask that you do not add your name or any Institution details to the CRUK EDI Recruitment Form

• Applications will be shortlisted initially based on the CRUK EDI Recruitment Form only. CVs will be used in further rounds of shortlisting to invite candidates to interview.

Relevant Publications

1. Madsen RR, Vanhaesebroeck, B, Semple, RK. Cancer-Associated PIK3CA Mutations in Overgrowth DisordersCancer-Associated PIK3CA Mutations in Overgrowth Disorders. Trends in Molecular Medicine. 2018;24(10):856–870.
2. Mruk O & Madsen RR*. PI3K inhibitor-free differentiation and maturation of human iPSC-derived arterialand venous-like endothelial cells. bioRxiv. 2026. 
3. Blanch-Asensio, A. et al. STRAIGHT-IN Dual: a platform for dual, single-copy integrations of DNA payloads and gene circuits into human induced pluripotent stem cells. Preprint at https://doi.org/10.1101/2024.10.17.616637 (2024).
4. Hillis AL, Martin TD, Manchester HE, Hogstrom JM, Zhang N, Lecky E, Kozlova N, Persky NS, Root DE, Brown M, Cichowski K, Elledge SJ, Muranen T, Fruman DA, Barry ST, Clohessy JG, Madsen RR, Toker A. Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer. Cancer Research. 2024;84(19):3250-3266. 
5. Madsen RR*, Le Marois A, Mruk O, Voliotis M, Yin S, Sufi J, Qin X, Zhao SJ, Gorczynska J, Morelli D, Davidson L, Sahai E, Korolchuk VI, Tape CJ, Vanhaesebroeck B. Oncogenic PIK3CA corrupts growth factor signaling specificity. Molecular Systems Biology. 2024; 21:126-157.