Laboratory of Angiogenesis and Vascular Metabolism

Peter Carmeliet’s laboratory focuses on one central topic ”Angiogenesis”, the growth of new blood vessels, in health and disease. Abnormal blood vessel growth, excessive or insufficient, contributes to multiple disorders, including cardiovascular disease, diabetes, cancer, age-related blindness, stroke, etc. Our ambition is to develop therapeutic concepts and, if possible, innovative anti-angiogenic treatments.

Latest findings indicate that the efficacy of current anti-angiogenic therapy (targeting VEGF) in cancer is limited by intrinsic refractoriness and acquired drug resistance. There is thus an urgent medical need to improve clinical anti-angiogenic therapy. To remedy this problem, Peter Carmeliet’s team uses a fundamentally distinct approach and pioneered the study of endothelial cell (EC) metabolism during angiogenesis, hypothesizing that targeting the metabolic “engine” of ECs would paralyze blood vessel growth and normalize tumor vessels. The role of several key metabolic targets in endothelial cell biology and tumor angiogenesis are currently studied, also at the single cell level.

The Carmeliet lab is also interested in unraveling the molecular basis of EC dysfunction and EC regeneration. EC dysfunction is of utmost importance in diseases such as diabetes, metabolic syndrome, etc., as it is a key determinant of cardiovascular morbidity and mortality, even when glycemia levels are under control. In fact, when becoming dysfunctional, the endothelium contributes to more (cardiovascular) diseases than any other cell type.

The team applies standard (conditional gene targeting/silencing/overexpression) as well as sophisticated novel disruptive high-throughput multi-omics approaches (bulk and scRNAseq, scG&T, scATAC; metabolomics, etc.) and computational modeling, both for hypothesis generation and hypothesis testing experiments. For instance, successful efforts in generating a single cell transcriptome atlas of ECs from various healthy and pathological (including tumor) tissues from preclinical models and clinical samples has revealed the existence of previously unknown EC subtypes, including ECs with a resident endothelial stem cell signature, and EC with a putative immunosurveillance role, key findings being taken into further investigation. In addition, EC-specific Genome scale metabolic models (GEM) were generated and successfully used to predict metabolic enzymes/pathways essential for endothelial cell growth.

 

Current fundamental and translational topics:

  • Endothelial cell heterogeneity between and within healthy tissues, tumor types or other diseased tissues/organs
  • Immune surveillance role of the endothelium
  • Development of tumor EC specific genome-scale metabolic models (GEMs) to predict tumor-tailored endothelial metabolic targets and define approaches to overcome resistance to current anti-angiogenesis therapy
  • Analysis by single cell analysis of different modes of blood vessel formation in cancer and other pathologies (angiogenesis, vessel cooption, intussusceptive growth), their relative contribution and importance in different tissues and different conditions, and the underlying regulatory mechanisms
  • Functional validation of candidate (metabolic) anti-angiogenesis targets defined by transcriptomic analysis and in silico GEM prediction
  • Drug development against candidate EC metabolic targets, identified in prior work by the lab
  • Studies into regenerative medicine approaches for kidney disease/kidney transplantation and liver regeneration
  • Molecular regulation of cellular interactions between perivascular macrophages and tumor endothelial cells involved in immune reactions against solid tumors (with Montis Biosciences, a spin-off of KU Leuven and VIB with Droia Ventures, based on research findings of the Carmeliet and Mazzone labs)
  • To apply the in-house developed bioinformatics software platform (BIOMEX) and machine learning to identify metabolic biomarker signatures that predict chemotherapy and immunotherapy response in different cancer patients.
  • Clinical phase II trial to test ketogenic diet to promote lymphatic growth / function in lymphedema patients (UZ Hospital Leuven)
  • Analysis of the role and therapeutic targetability of the lung endothelium in COVID-19 disease, and development of new diagnostic and predictive COVID-19 tests and therapies.

 

 

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wordleTHE WORK OF PETER CARMELIET IS SUPPORTED BY:

Funding