Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution
- Mol Cancer. 2023 Jan 24;22(1):17. doi: 10.1186/s12943-023-01713-1.
- 1. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075, Göttingen, Germany.
- 2. Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075, Göttingen, Germany.
- 3. German Center for Cardiovascular Research (DZHK), Partner Site, Göttingen, Germany.
- 4. Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Straβe40, 37075, Göttingen, Germany.
- 5. Department of Oncology, Antwerp University Hospital (UZA), Drie Eikenstraat 655, 2650, Edegem, Belgium.
- 6. Department of General- and Visceral Surgery, Raphaelsklinik Münster, Loerstraße 23, 48143, Münster, Germany.
- 7. Department of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077, Göttingen, Germany.
- 8. Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149, Münster, Germany.
- 9. Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
- 10. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
- 11. Translational Cancer Research Unit, GZA Hospitals, Sint-Augustinus, University of Antwerp, Antwerp, Belgium.
- 12. Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000, Aarhus C, Denmark.
- 13. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
- 14. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075, Göttingen, Germany. [email protected].
- # Contributed equally.
Background: Colorectal Cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while Others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood.
Methods: We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA Sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived Organoid cultures.
Results: We detected specific metabolic alterations and a signature of Wnt signalling activation in metastatic Cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis.
Conclusion: These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.