# Senescence caused by telomerase inactivation in myeloid, mesenchymal, and endothelial cells has distinct effects on cancer progression

## TL;DR

This study shows that cell senescence in different parts of the tumor environment affects cancer progression differently, with endothelial cell senescence being especially important for preventing metastasis.

## Contribution

The paper reveals distinct effects of telomerase inactivation in specific tumor microenvironment cell types on cancer progression and metastasis.

## Key findings

- Senescence in myeloid and mesenchymal cells increased tumor fibrosis and desmoplasia.
- Endothelial cell senescence reduced tumor vascularization and increased hypoxia markers.
- Endothelial cell function preservation was crucial for suppressing liver metastases in KPC tumors.

## Abstract

The effects of cell senescence in individual cell populations of the tumor microenvironment (TME) on cancer progression remain unclear. Here, we investigated the effects of cell senescence caused by inactivation of the catalytic subunit of telomerase (Tert) in distinct TME components. We generated genetic Tert knockout (KO) mice driven by the LysM promoter in myeloid cells, by the Pdgfra or Pdgfrb promoter in mesenchymal cells, and by the Tie2e promoter in endothelial cells. We compared the effect of the Tert KOs in syngeneic models of orthotopically grafted E0771 breast adenocarcinoma, RM1 prostate adenocarcinoma, and KPC pancreatic adenocarcinoma. Tumors in LysM-Tert-KO, Pdgfra-Tert-KO, and Pdgfrb-Tert-KO mice displayed increased myofibrogenesis and desmoplasia. Tumors in Tie2e-Tert-KO mice displayed endothelial abnormality and the strongest reduction in tumor vascularization. This was linked with increased HIF1a protein nuclear localization, indicative of hypoxia, and the highest protein expression of the glycolytic marker GLUT1 in cancer cells. KPC tumors displayed reduced epithelial cytokeratin-19 protein expression and reduced tumor growth in all Tert KO models. However, liver metastases of KPC cells were only observed for Tie2e-Tert-KO mice. We conclude that senescence of distinct cells in the TME has different effects on cancer progression and that endothelial cell function preservation is important in metastasis suppression.