Aging triggers a pro-tumorigenic senescent lung microenvironment

29 May 26

Presentation

Organizer: IRB BioMed Seminars

Date / Time: Friday, May 29th at 12:00
Place: Auditorium Room

Speaker: Daniel Muñoz-Espin, PhD - Group Leader ECI - Co-lead of Thoracic Cancer Programme - CRUK Cambridge Centre - Early Cancer Institute (ECI)- Department of Oncology, University of Cambridge.

Hosts: Marco Milán, Ph.D. - Programme Chair - Group Leader, IRB Barcelona - Mechanisms of Disease Programme
and, Direna Alonso-Curbelo, Ph.D. - Group Leader, IRB Barcelona - Cancer Science Programme.

Aging triggers a pro-tumorigenic senescent lung microenvironment

Diana Campos-Iglesias^1,2,#, Joaquín Araos Henríquez^1,2,#, Jianfeng Ge^1,2, Robert Rintoul², Scott Haston³, Juan Pedro Martinez-Barbera³, Daniel Muñoz-Espín^1,2,^*

¹Early Cancer Institute, Department of Oncology, University of Cambridge, UK

²CRUK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK

³UCL Great Ormond Street Institute of Child Health, London, UK

^* Leading author

^#These authors contributed equally

Abstract

Lung adenocarcinoma (LUAD) is a disease of unmet need due to its high lethality and limited therapeutic options. In a previous study, we found a population of senescence macrophages playing a fundamental role in lung carcinogenesis and, notably, accumulating in naturally aged lungs in the absence of oncogenic stress. While the incidence of LUAD increases with age, the composition of an aged microenvironment and how it relates to lung cancer initiation and progression remains poorly understood.

Here, we investigated how ageing modulates the landscape of senescent cells (SnCs) in normal lungs prior tumour initiation and during early stages of carcinogenesis. To address this, we employed young (~3-months-old) and aged (~18-months-old) p16-FDR mice. In this model, mCherry and the diphtheria toxin receptor (DTR) are expressed under the control of the Cdkn2a promoter (encoding for p16^INK4A) to selectively trace and eliminate SnCs in vivo. By leveraging three mouse models of LUAD based on the p16-FDR allele, including genetically-engineered mice (Kras^G12D), orthotopic transplantation of KP cells (Kras^G12D;Trp53^fl/fl) and carcinogen-induced LUAD using N-methyl-N-nitrosourea, we show that the selective ablation of SnCs in aged lungs ameliorates tumorigenesis. Our results highlight the role of ageing on shaping a microenvironment featured by immune senescent cells, including specific populations of macrophages and dendritic cells.

This study has important implications for the identification of early carcinogenesis biomarkers and novel strategies for lung cancer prevention and interception in high-risk individuals.

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