Although smoking is a major risk factor in developing lung cancer, in people who have never smoked, lung cancer is still the 7th most prevalent cancer worldwide. This may be partly explained by exposure to air pollution, another risk factor for lung cancer, but recent studies have failed to detect signatures of pollution-induced mutations in non-smokers with lung cancer. Moreover, it is now well appreciated that many of the same driver mutations found in tumors, such as mutated epidermal growth factor receptor (EGFR) are often found in people who will never go on to develop lung cancer. These results complicate the model that chemical carcinogens cause cancer solely by mutating cancer-driving genes, and suggest that they may have other effects which promote tumor formation and growth.
In this ASPIRE award, Charles Swanton and his team will test the hypothesis that while oncogenic EGFR mutations can and do occur in normal tissue, they are not sufficient for cancer growth alone. The team posits that tissue and cells with such mutations must also be triggered in some way by carcinogenic environmental factors to promote remodeling of the cellular microenvironment which activates tumor formation. Swanton’s team will measure the presence and expansion of cells with mutant EGFR in normal tissues and assess whether these correlate with various parameters, including air pollution, cigarette smoke exposure, and gender. They then plan to characterize alterations in the lung microenvironment that may initiate cancer development and functionally validate candidates that drive selection of mutant clones in normal tissues. Understanding how environmental factors can trigger cancer in the absence of a mutagenic signature may provide alternative therapeutic approaches and novel risk factors for cancer prevention, diagnosis, and treatments.
published research
Bailey C, Pich O, Thol K, Watkins TBK, Luebeck J, Rowan A, Stavrou G, Weiser NE, Dameracharla B, Bentham R, Lu WT, Kittel J, Yang SYC, Howitt BE, Sharma N, Litovchenko M, Salgado R, Hung KL, Cornish AJ, Moore DA, Houlston RS, Bafna V, Chang HY, Nik-Zainal S, Kanu N, McGranahan N; Genomics England Consortium; Flanagan AM, Mischel PS, Jamal-Hanjani M, Swanton C. Origins and impact of extrachromosomal DNA. Nature. 2024.
Puttick C, Jones TP, Leung MM, Galvez-Cancino F, Liu J, Varas-Godoy M, Rowan A, Pich O, Martinez-Ruiz C, Bentham R, Dijkstra KK, Black JRM, Rosenthal R, Kanu N, Litchfield K, Salgado R, Moore DA, Van Loo P, Jamal-Hanjani M, Quezada SA; TRACERx Consortium; Swanton C, McGranahan N. MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution. Nat Genet. 2024.
Hill W, Weeden CE, Swanton C. Tumor Promoters and Opportunities for Molecular Cancer Prevention. Cancer Discov. 2024.
Dietzen M, Zhai H, Lucas O, Pich O, Barrington C, Lu WT, Ward S, Guo Y, Hynds RE, Zaccaria S, Swanton C, McGranahan N, Kanu N. Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution. Nat Commun. 2024.
Boire A, Burke K, Cox TR, Guise T, Jamal-Hanjani M, Janowitz T, Kaplan R, Lee R, Swanton C, Vander Heiden MG, Sahai E. Why do patients with cancer die? Nat Rev Cancer. 2024.
Magness A, Colliver E, Enfield KSS, Lee C, Shimato M, Daly E, Moore DA, Sivakumar M, Valand K, Levi D, Hiley CT, Hobson PS, van Maldegem F, Reading JL, Quezada SA, Downward J, Sahai E, Swanton C, Angelova M. Deep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX. Nat Commun. 2024.
Hobor S, Al Bakir M, Hiley CT, Skrzypski M, Frankell AM, Bakker B, Watkins TBK, Markovets A, Dry JR, Brown AP, van der Aart J, van den Bos H, Spierings D, Oukrif D, Novelli M, Chakrabarti T, Rabinowitz AH, Ait Hassou L, Litière S, Kerr DL, Tan L, Kelly G, Moore DA, Renshaw MJ, Venkatesan S, Hill W, Huebner A, Martínez-Ruiz C, Black JRM, Wu W, Angelova M, McGranahan N, Downward J, Chmielecki J, Barrett C, Litchfield K, Chew SK, Blakely CM, de Bruin EC, Foijer F, Vousden KH, Bivona TG; TRACERx consortium; Hynds RE, Kanu N, Zaccaria S, Grönroos E, Swanton C. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nat Commun. 2024.
Hynds RE, Huebner A, Pearce DR, Hill MS, Akarca AU, Moore DA, Ward S, Gowers KHC, Karasaki T, Al Bakir M, Wilson GA, Pich O, Martínez-Ruiz C, Hossain ASMM, Pearce SP, Sivakumar M, Ben Aissa A, Grönroos E, Chandrasekharan D, Kolluri KK, Towns R, Wang K, Cook DE, Bosshard-Carter L, Naceur-Lombardelli C, Rowan AJ, Veeriah S, Litchfield K, Crosbie PAJ, Dive C, Quezada SA, Janes SM, Jamal-Hanjani M, Marafioti T; TRACERx consortium; McGranahan N, Swanton C. Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models. Nat Commun. 2024.
Enfield KSS, Colliver E, Lee CSY, Magness A, Moore DA, Sivakumar M, Grigoriadis K, Pich O, Karasaki T, Hobson PS, Levi D, Veeriah S, Puttick C, Nye EL, Green M, Dijkstra KK, Shimato M, Akarca AU, Marafioti T, Salgado R, Hackshaw A, Consortium T, Jamal-Hanjani M, van Maldegem F, McGranahan N, Glass B, Pulaski H, Walk E, Reading JL, Quezada SA, Hiley CT, Downward J, Sahai E, Swanton C, Angelova M. Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer. Cancer Discov. 2024.
Pan X, AbdulJabbar K, Coelho-Lima J, Grapa AI, Zhang H, Cheung AHK, Baena J, Karasaki T, Wilson CR, Sereno M, Veeriah S, Aitken SJ, Hackshaw A, Nicholson AG, Jamal-Hanjani M; TRACERx Consortium; Swanton C, Yuan Y, Le Quesne J, Moore DA. The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma. Nat Cancer. 2024.
Pearce DR, Akarca AU, De Maeyer RPH, Kostina E, Huebner A, Sivakumar M, Karasaki T, Shah K, Janes SM, McGranahan N, Reddy V, Akbar AN, Moore DA, Marafioti T, Swanton C, Hynds RE. Phenotyping of lymphoproliferative tumours generated in xenografts of non-small cell lung cancer. Front Oncol. 2023.
Zhang H, AbdulJabbar K, Moore DA, Akarca A, Enfield KSS, Jamal-Hanjani M, Raza SEA, Veeriah S, Salgado R, McGranahan N, Le Quesne J, Swanton C, Marafioti T, Yuan Y. Spatial Positioning of Immune Hotspots Reflects the Interplay between B and T Cells in Lung Squamous Cell Carcinoma. Cancer Res. 2023.
Weeden CE, Gayevskiy V, Marceaux C, Batey D, Tan T, Yokote K, Ribera NT, Clatch A, Christo S, Teh CE, Mitchell AJ, Trussart M, Rankin LC, Obers A, McDonald JA, Sutherland KD, Sharma VJ, Starkey G, D’Costa R, Antippa P, Leong T, Steinfort D, Irving L, Swanton C, Gordon CL, Mackay LK, Speed TP, Gray DHD, Asselin-Labat ML. Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer. Cancer Cell. 2023.
Karasaki T, Moore DA, Veeriah S, Naceur-Lombardelli C, Toncheva A, Magno N, Ward S, Bakir MA, Watkins TBK, Grigoriadis K, Huebner A, Hill MS, Frankell AM, Abbosh C, Puttick C, Zhai H, Gimeno-Valiente F, Saghafinia S, Kanu N, Dietzen M, Pich O, Lim EL, Martínez-Ruiz C, Black JRM, Biswas D, Campbell BB, Lee C, Colliver E, Enfield KSS, Hessey S, Hiley CT, Zaccaria S, Litchfield K, Birkbak NJ, Cadieux EL, Demeulemeester J, Van Loo P, Adusumilli PS, Tan KS, Cheema W, Sanchez-Vega F, Jones DR, Rekhtman N, Travis WD, Hackshaw A, Marafioti T, Salgado R, Le Quesne J, Nicholson AG; TRACERx Consortium; McGranahan N, Swanton C, Jamal-Hanjani M. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx. Nat Med. 2023.
Al-Sawaf O, Weiss J, Skrzypski M, Lam JM, Karasaki T, Zambrana F, Kidd AC, Frankell AM, Watkins TBK, Martínez-Ruiz C, Puttick C, Black JRM, Huebner A, Bakir MA, Sokač M, Collins S, Veeriah S, Magno N, Naceur-Lombardelli C, Prymas P, Toncheva A, Ward S, Jayanth N, Salgado R, Bridge CP, Christiani DC, Mak RH, Bay C, Rosenthal M, Sattar N, Welsh P, Liu Y, Perrimon N, Popuri K, Beg MF, McGranahan N, Hackshaw A, Breen DM, O’Rahilly S, Birkbak NJ, Aerts HJWL; TRACERx Consortium; Jamal-Hanjani M, Swanton C. Body composition and lung cancer-associated cachexia in TRACERx. Nat Med. 2023.
Frankell AM, Dietzen M, Al Bakir M, Lim EL, Karasaki T, Ward S, Veeriah S, Colliver E, Huebner A, Bunkum A, Hill MS, Grigoriadis K, Moore DA, Black JRM, Liu WK, Thol K, Pich O, Watkins TBK, Naceur-Lombardelli C, Cook DE, Salgado R, Wilson GA, Bailey C, Angelova M, Bentham R, Martínez-Ruiz C, Abbosh C, Nicholson AG, Le Quesne J, Biswas D, Rosenthal R, Puttick C, Hessey S, Lee C, Prymas P, Toncheva A, Smith J, Xing W, Nicod J, Price G, Kerr KM, Naidu B, Middleton G, Blyth KG, Fennell DA, Forster MD, Lee SM, Falzon M, Hewish M, Shackcloth MJ, Lim E, Benafif S, Russell P, Boleti E, Krebs MG, Lester JF, Papadatos-Pastos D, Ahmad T, Thakrar RM, Lawrence D, Navani N, Janes SM, Dive C, Blackhall FH, Summers Y, Cave J, Marafioti T, Herrero J, Quezada SA, Peggs KS, Schwarz RF, Van Loo P, Miedema DM, Birkbak NJ, Hiley CT, Hackshaw A, Zaccaria S; TRACERx Consortium; Jamal-Hanjani M, McGranahan N, Swanton C. The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature. 2023.
Martínez-Ruiz C, Black JRM, Puttick C, Hill MS, Demeulemeester J, Larose Cadieux E, Thol K, Jones TP, Veeriah S, Naceur-Lombardelli C, Toncheva A, Prymas P, Rowan A, Ward S, Cubitt L, Athanasopoulou F, Pich O, Karasaki T, Moore DA, Salgado R, Colliver E, Castignani C, Dietzen M, Huebner A, Al Bakir M, Tanić M, Watkins TBK, Lim EL, Al-Rashed AM, Lang D, Clements J, Cook DE, Rosenthal R, Wilson GA, Frankell AM, de Carné Trécesson S, East P, Kanu N, Litchfield K, Birkbak NJ, Hackshaw A, Beck S, Van Loo P, Jamal-Hanjani M; TRACERx Consortium; Swanton C, McGranahan N. Genomic-transcriptomic evolution in lung cancer and metastasis. Nature. 2023.
Ng KW, Boumelha J, Enfield KSS, Almagro J, Cha H, Pich O, Karasaki T, Moore DA, Salgado R, Sivakumar M, Young G, Molina-Arcas M, de Carné Trécesson S, Anastasiou P, Fendler A, Au L, Shepherd STC, Martínez-Ruiz C, Puttick C, Black JRM, Watkins TBK, Kim H, Shim S, Faulkner N, Attig J, Veeriah S, Magno N, Ward S, Frankell AM, Al Bakir M, Lim EL, Hill MS, Wilson GA, Cook DE, Birkbak NJ, Behrens A, Yousaf N, Popat S, Hackshaw A; TRACERx Consortium; CAPTURE Consortium; Hiley CT, Litchfield K, McGranahan N, Jamal-Hanjani M, Larkin J, Lee SH, Turajlic S, Swanton C, Downward J, Kassiotis G. Antibodies against endogenous retroviruses promote lung cancer immunotherapy. Nature. 2023.
Al Bakir M, Huebner A, Martínez-Ruiz C, Grigoriadis K, Watkins TBK, Pich O, Moore DA, Veeriah S, Ward S, Laycock J, Johnson D, Rowan A, Razaq M, Akther M, Naceur-Lombardelli C, Prymas P, Toncheva A, Hessey S, Dietzen M, Colliver E, Frankell AM, Bunkum A, Lim EL, Karasaki T, Abbosh C, Hiley CT, Hill MS, Cook DE, Wilson GA, Salgado R, Nye E, Stone RK, Fennell DA, Price G, Kerr KM, Naidu B, Middleton G, Summers Y, Lindsay CR, Blackhall FH, Cave J, Blyth KG, Nair A, Ahmed A, Taylor MN, Procter AJ, Falzon M, Lawrence D, Navani N, Thakrar RM, Janes SM, Papadatos-Pastos D, Forster MD, Lee SM, Ahmad T, Quezada SA, Peggs KS, Van Loo P, Dive C, Hackshaw A, Birkbak NJ, Zaccaria S; TRACERx Consortium; Jamal-Hanjani M, McGranahan N, Swanton C. The evolution of non-small cell lung cancer metastases in TRACERx. Nature. 2023.
Abbosh C, Frankell AM, Harrison T, Kisistok J, Garnett A, Johnson L, Veeriah S, Moreau M, Chesh A, Chaunzwa TL, Weiss J, Schroeder MR, Ward S, Grigoriadis K, Shahpurwalla A, Litchfield K, Puttick C, Biswas D, Karasaki T, Black JRM, Martínez-Ruiz C, Bakir MA, Pich O, Watkins TBK, Lim EL, Huebner A, Moore DA, Godin-Heymann N, L’Hernault A, Bye H, Odell A, Roberts P, Gomes F, Patel AJ, Manzano E, Hiley CT, Carey N, Riley J, Cook DE, Hodgson D, Stetson D, Barrett JC, Kortlever RM, Evan GI, Hackshaw A, Daber RD, Shaw JA, Aerts HJWL, Licon A, Stahl J, Jamal-Hanjani M; TRACERx Consortium; Birkbak NJ, McGranahan N, Swanton C. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature. 2023.
Weeden CE, Hill W, Lim EL, Grönroos E, Swanton C. Impact of risk factors on early cancer evolution. Cell. 2023.
Hill W, Lim EL, Weeden CE, Lee C, Augustine M, Chen K, Kuan FC, Marongiu F, Evans EJ Jr, Moore DA, Rodrigues FS, Pich O, Bakker B, Cha H, Myers R, van Maldegem F, Boumelha J, Veeriah S, Rowan A, Naceur-Lombardelli C, Karasaki T, Sivakumar M, De S, Caswell DR, Nagano A, Black JRM, Martínez-Ruiz C, Ryu MH, Huff RD, Li S, Favé MJ, Magness A, Suárez-Bonnet A, Priestnall SL, Lüchtenborg M, Lavelle K, Pethick J, Hardy S, McRonald FE, Lin MH, Troccoli CI, Ghosh M, Miller YE, Merrick DT, Keith RL, Al Bakir M, Bailey C, Hill MS, Saal LH, Chen Y, George AM, Abbosh C, Kanu N, Lee SH, McGranahan N, Berg CD, Sasieni P, Houlston R, Turnbull C, Lam S, Awadalla P, Grönroos E, Downward J, Jacks T, Carlsten C, Malanchi I, Hackshaw A, Litchfield K; TRACERx Consortium; DeGregori J, Jamal-Hanjani M, Swanton C. Lung adenocarcinoma promotion by air pollutants. Nature. 2023.
Spain L, Coulton A, Lobon I, Rowan A, Schnidrig D, Shepherd STC, Shum B, Byrne F, Goicoechea M, Piperni E, Au L, Edmonds K, Carlyle E, Hunter N, Renn A, Messiou C, Hughes P, Nobbs J, Foijer F, van den Bos H, Wardenaar R, Spierings DCJ, Spencer C, Schmitt AM, Tippu Z, Lingard K, Grostate L, Peat K, Kelly K, Sarker S, Vaughan S, Mangwende M, Terry L, Kelly D, Biano J, Murra A, Korteweg J, Lewis C, OFlaherty M, Cattin AL, Emmerich M, Gerard CL, Pallikonda HA, Lynch J, Mason R, Rogiers A, Xu H, Huebner A, McGranahan N, Al Bakir M, Murai J, Naceur-Lombardelli C, Borg E, Mitchison M, Moore DA, Falzon M, Proctor I, Stamp GWH, Nye EL, Young K, Furness AJS, Pickering L, Stewart R, Mahadeva U, Green A, Larkin J, Litchfield K, Swanton C, Jamal-Hanjani M, Turajlic S. Late-stage metastatic melanoma emerges through a diversity of evolutionary pathways. Cancer Discov. 2023.
Jamshidi A, Liu MC, Klein EA, Venn O, Hubbell E, Beausang JF, Gross S, Melton C, Fields AP, Liu Q, Zhang N, Fung ET, Kurtzman KN, Amini H, Betts C, Civello D, Freese P, Calef R, Davydov K, Fayzullina S, Hou C, Jiang R, Jung B, Tang S, Demas V, Newman J, Sakarya O, Scott E, Shenoy A, Shojaee S, Steffen KK, Nicula V, Chien TC, Bagaria S, Hunkapiller N, Desai M, Dong Z, Richards DA, Yeatman TJ, Cohn AL, Thiel DD, Berry DA, Tummala MK, McIntyre K, Sekeres MA, Bryce A, Aravanis AM, Seiden MV, Swanton C. Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell. 2022.