Wilkinson, Simon

Frame, Margaret

Millar, Fraser Russell

2022-03-08T15:46:19Z

2022-03-08T15:46:19Z

2022-03-08

Lung cancer is the most lethal cancer type worldwide, with a mortality rate greater than breast, colorectal and prostate cancer combined. Targeting early-stage disease is widely recognised to improve overall survival, however the mechanisms and components of the early tumour suppressor response in lung cancer are not fully elucidated. In this thesis I present data from human samples as well as genetically engineered mouse models (GEMMs) demonstrating that the previously identified senescence regulator TLR2 orchestrates a potent anti-tumour response in non-small cell lung cancer. Mechanistically, TLR2 regulates both cell intrinsic senescence-associated cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP) that is integral in the immune surveillance of premalignant cells. TLR2 and the SASP are highly expressed in human lung cancer epithelium and correlate with clinical regression and improved survival. Importantly, pharmacological modulation of this pathway with a Tlr2 agonist significantly reduces lung tumour growth, highlighting a potential therapeutic target in early lung cancer.

https://hdl.handle.net/1842/38674

http://dx.doi.org/10.7488/era/1932

en

The University of Edinburgh

early lung cancer

senescent cells

TLR2

Toll-like receptor 2 orchestrates a novel tumour suppressor response in non-small cell lung cancer

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy