Identifying biomarkers and therapeutic targets in primary breast angiosarcoma using iPSC-derived endothelial models
Explore how co-occurring mutations in PIK3CA and KDR drive rare primary breast angiosarcoma using innovative iPSC-derived endothelial models. Generate new insights into tumor initiation, identify biomarkers, and test targeted therapies to advance diagnostics and treatment for this aggressive cancer.
AI-generated overview
Project Description
Project Overview
Primary breast angiosarcoma (PBA) is a rare, aggressive soft tissue tumour arising from endothelial cells. Characterized by frequent co-occurring activating mutations in PIK3CA and KDR genes, the disease lacks effective diagnostic markers and targeted therapies. This project will use human induced pluripotent stem cell (iPSC)-derived endothelial cells engineered to model these mutations to dissect oncogenic mechanisms and identify therapeutic vulnerabilities.
What You Will Do
The student will culture human iPSCs and differentiate them into arterial and venous endothelial cells, employing transposon-based inducible gene expression systems to introduce PIK3CA and KDR mutations individually and combined. They will apply lineage barcoding to trace transformation, perform multi-omics including single-cell mass cytometry (CyTOF), spatial transcriptomics, proteomics, and cytokine profiling. Functional assays include drug screening with clinically relevant compounds and evaluation of combination therapies.
Expected Outcomes
The project will reveal how oncogenic PIK3CA-KDR cooperativity remodels endothelial cell state, contribute to malignant transformation, and establish diagnostic biomarkers and therapeutic targets. These findings could enable new strategies for early diagnosis and targeted treatment of PBA, improving patient prognosis.
Why This Matters
PBA has poor survival rates and lacks established management protocols. Understanding the molecular and cellular basis of tumor initiation and progression is critical for developing better diagnostics and therapies. This work addresses a significant clinical and biological knowledge gap, potentially impacting personalized medicine for a rare but deadly cancer.
Eligibility
Supervisor Profile
Dr Ralitsa Madsen leads research at the Cancer Research UK Beatson Institute focusing on cancer cell biology, particularly vascular tumors like angiosarcoma. Her work integrates stem cell modeling, genetic engineering, and multi-omics to elucidate tumor mechanisms and identify therapeutic targets, positioning her at the forefront of disease modeling using iPSC technology.