Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.
Sergio Piñeiro-HermidaGiuseppe BossoRaúl Sánchez-VázquezPaula MartínezMaria A BlascoPublished in: Cell death and differentiation (2023)
Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8 + T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.
Keyphrases
- cell cycle arrest
- cell death
- small cell lung cancer
- pi k akt
- end stage renal disease
- advanced non small cell lung cancer
- oxidative stress
- copy number
- newly diagnosed
- signaling pathway
- dna damage response
- chronic kidney disease
- ejection fraction
- poor prognosis
- peritoneal dialysis
- mitochondrial dna
- prognostic factors
- mouse model
- endoplasmic reticulum stress
- squamous cell carcinoma
- replacement therapy
- cell proliferation
- induced apoptosis
- skeletal muscle
- epidermal growth factor receptor
- binding protein
- young adults
- high fat diet induced
- dna damage
- combination therapy
- dna repair
- wild type