Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution

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.

Vessel co-option: a unique vascular-immune niche in liver cancer

“…Studies suggest that AAT usually induces hypoxia microenvironment before tumoracquired drug resistance, which is beneficial to the transformation of tumor metabolism to glycolysis and glutamine metabolism (48)(49)(50). In VC, the tumor tissue showed enhanced glycolysis and pentose phosphate pathway activation (51). The pentose phosphate pathway has the function of anti-oxidation and defense and has a higher resistance to reactive oxygen species.…”

Expression profile and prognostic value of the circadian clock in clear cell renal cell carcinoma

“…We performed univariate and multivariate Cox regression analyses for overall survival (OS) in previously described TCGA datasets [37]. As a statistical threshold, a false discovery rate (FDR) < 0.05 was utilized.…”

Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application

“…Among metastatic sites, the liver is the most frequent, accounting for approximately 60% of all metastatic colorectal cancer (mCRC) cases [ 4 ]. Despite advancements in treatment, mCRC continues to pose substantial lethality, with a 5-year survival rate of approximately 14% [ 5 , 6 ]. Therefore, the identification of effective treatment options to enhance the survival and quality of life of patients with mCRC is imperative.…”