2. Academic Validation
  3. Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution

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.
Johannes Robert Fleischer # 1,  Alexandra Maria Schmitt # 1,  Gwendolyn Haas # 1,  Xingbo Xu 2 3,  Elisabeth Maria Zeisberg 2 3,  Hanibal Bohnenberger 4,  Stefan Küffer 4,  Laure-Anne Teuwen 5,  Philipp Johannes Karras 1 6,  Tim Beißbarth 7,  Annalen Bleckmann 8,  Mélanie Planque 9 10,  Sarah-Maria Fendt 9 10,  Peter Vermeulen 11,  Michael Ghadimi 1,  Joanna Kalucka 12 13,  Tiago De Oliveira # 1,  Lena-Christin Conradi # 14
Affiliations

Affiliations

  • 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.
PMID: 36691028 DOI: 10.1186/s12943-023-01713-1
Abstract

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.

Keywords

Colorectal cancer liver metastases; Glycolysis; Histopathological growth patterns; Pentose phosphate pathway; Sprouting angiogenesis; Vessel co-option; WNT signalling.

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