Abstract
Background
Platelet-tumor endothelial cell interactions are pivotal in the colorectal cancer microenvironment, driving tumor invasion, metastasis and shaping the immune landscape. Investigating these interactions sheds light on the underlying mechanisms of colorectal cancer progression and opens avenues for novel therapeutic interventions.
Methods
By interrogating 10x Genomics single-cell transcriptomic data from 23 publicly available samples, we constructed a paired cancerous and adjacent non-cancerous single-cell atlas for colorectal cancer (CRC). Utilizing a comprehensive suite of analyses, including area under the curve (AUC), copy number variation, pseudotime trajectory, enrichment, and intercellular communication assessments, we delineated the heterogeneity within CRC endothelial cells. Furthermore, our SCENIC transcription factor analysis pinpointed the most active transcription factors within the platelet-associated endothelial cell subpopulation. The functional relevance of TRAF4 in endothelial cell was subsequently confirmed by in vitro validation and large cohort clinical samples.
Results
We delineated a distinct subpopulation of endothelial cells, designated as C2, that is profoundly influenced by platelet education and is intricately linked to tumor metastasis, adverse prognosis, and immune cell infiltration. This subpopulation exhibits a strong association with the immune cell infiltration characteristic of the tumor microenvironment. Notably, TRAF4 emerged as a pivotal platelet-related transcription factors within this subgroup, with its downregulation leading to diminished migration, angiogenic potential, and chemotactic responsiveness of endothelial cells to CD8 + T cells. Additionally, the expression of TRAF4 and its correlation with CD8 + T cell infiltration were corroborated in clinical specimens.
Conclusions
Our investigation has identified a platelet-associated subpopulation of tumor endothelial cells that contributes to the suppression of CD8 + T cell infiltration within the tumor microenvironment and promotes tumor angiogenesis, thereby facilitating malignant tumor progression. Furthermore, we have pinpointed TRAF4 as a pivotal transcription factor within this subpopulation, underscoring its significant promise as an innovative therapeutic target for CRC.