Endothelial Cell Cycle Control and Specification in the Tumor Vasculature 62 views

Tumor blood vessels are dysfunctional, impairing immune cell infiltration and drug delivery and promoting hypoxia that selects for aggressive cancer cells. Therapeutic strategies target angiogenic factors to normalize the tumor vasculature but often result in a small window of efficacy due to resistance or over-pruning. We found that distinct endothelial cell (EC) cycle states (early G1 vs. late G1) are required for EC specification into venous vs. arterial subtypes, respectively. In addition, we found that EC cycle control and specification were dysregulated in vascular malformations that resembled tumor vasculature. These malformations were prevented by treatment with palbociclib, an FDA-approved CDK4/6 inhibitor used for breast cancer treatment. Yet, the effects of palbociclib, or other cell cycle inhibitors, on tumor vasculature were unknown. Through our work, we found EC cycle state is dysregulated in the tumor microenvironment and specification is impaired. In mice with induced mammary tumors, the proportion of proliferating tumor ECs was significantly increased and the proportion in late G1 was significantly decreased compared to healthy mammary ECs. Isolated tumor ECs exhibited decreased expression of arterial- and venous-enriched genes, indicating immature vessels. In mice with induced mammary and melanoma tumors, palbociclib treatment significantly decreased the proportion of proliferating ECs and increased the proportion of ECs in late G1. Functional studies and single-cell RNA-sequencing suggest palbociclib enhanced arterial-venous specification, normalized tumor EC metabolism, increased vessel perfusion and decreased tumor hypoxia. Extended treatment significantly increased pericyte coverage, a key indicator of vessel maturity. Finally, combined palbociclib treatment and immunotherapy improved the immune landscape and enabled enhanced CD8+ T cell infiltration into the tumor core. Thus, cell cycle inhibitors have the potential to mature tumor vasculature.

PHD (Doctor of Philosophy)

vasculature; endothelium; tumor; cell cycle

English

2026-10-16