Targeting Senescence in Lung Cancer: Novel Cancer Preventative and Therapeutic Opportunities
Early Cancer Institute, University of Cambridge (Co-Director of CRUK Cambridge Centre Thoracic Cancer Programme Department of Oncology)
Cellular senescence is a response to oncogene activation and therapy-induced genotoxic stress causing a stable cell cycle arrest. Importantly, recent evidence points to senescence and its associated inflammatory secretory phenotype (SASP) as a potential contributor to a variety of tumour-promoting activities and treatment resistance, although its impact in lung cancer development remains largely unknown.
Recently, by functional, confocal microscopy and scRNAseq analyses, we have found and dissected specific populations of the lung tumour microenvironment (TME), in particular immune system populations and vascular cells generating a niche of immunosuppression that facilitates lung cancer onset and progression. In vivo analyses eradicating TME senescent cells by pharmacogenetic and pharmacological approaches significantly reduces the tumour burden. Interestingly, these populations of tumour-promoting senescent immune system cells are conserved in naturally-aged mice.
In advanced adenocarcinomas, we have dissected the impact of different standard of care chemotherapies and show that chemo-induced SASP leads to and increased rate of proliferation, migration, metabolic rewiring and gain of malignant traits in recipient lung cancer cells. In vivo analyses demonstrate that chemotherapy-induced senescent cells strongly promote tumour progression in xenografts, orthotopic transplantation and endogenous KRASG12V-driven models of lung cancer. RNAseq profiling and proteomics analyses allowed us to identify the molecular mechanisms and key tumour-promoting SASP factors driving these effects. Concomitant pharmacologic inhibition of the responsible signalling pathways significantly prevented tumour-promoting effects driven by chemo-induced senescence and increased survival in mice.
Our results, additionally validated with human tissue samples, provide insights into the tissue microenvironment landscape, crucial cellular types contributing to the initiation, progression, and relapse of lung cancer, and their underlying mechanisms. These studies open potential therapeutic avenues, including cancer preventative strategies and combination therapies, for the management of lung cancer.