Cell migration sculpts evolutionary dynamics favouring therapy resistance in lung cancer
The evolution of cancer undermines the long-term efficacy of therapy. In this study, we combine experimental, computational, and clinical data analysis to investigate factors influencing the competition of subclones in lung cancer. Lineage tracing reveals unexpected variation in the long-term fate of neutral subclones, with subclones arising near the edge of tumours being favoured. Low levels of cell migration and cell mixing lead to high cell densities in the interior of the tumour that suppress proliferation. Using agent-based modelling and in silico analysis we inferred the extent of cell mixing in human tumours from the TRACERx lung cancer study. This reveals correlations between Epithelial to Mesenchymal Transition (EMT), stromal fibroblasts and levels of cell mixing. Experimental analysis confirms that both TGFβ-driven EMT and stromal fibroblasts reduce the variability in subclone fate and promote subclone mixing. Moreover, mixing favours clonal sweeps by subclones resistant to therapy-induced cell killing. Together, these analyses demonstrate that EMT and stromal fibroblasts sculpt tumour evolution by promoting cell mixing and thereby favour the rapid dominance of therapy resistant subclones.Competing Interest StatementD.B. reports personal fees from NanoString and AstraZeneca, and has a patent PCT/GB2020/050221 issued on methods for cancer prognostication. C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc - collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, and Personalis. He is Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee Chair. He is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAILs Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre, Shanghai, Metabomed (until July 2022), and the Sarah Cannon Research Institute C.S has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer, and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S declares a patent application (PCT/US2017/028013) for methods to lung cancer); targeting neoantigens (PCT/EP2016/059401); identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004); predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912); methods for lung cancer detection (US20190106751A1). C.S. is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity and under their terms of employment C.S is due a revenue share of any revenue generated from such license(s). E.S receives research funding from Merck Sharp Dohme, Astrazeneca, consults for Theolytics, and is on the scientific advisory board of Phenomic AI. The Francis Crick Institute, https://ror.org/04tnbqb63, CC2040, CC2041European Research Council, 101019366Japan Society for the Promotion of Science London, 201860634Wellcome Trust, WT209199/Z/17/ZCancer Research UK, C11496/A17786