The role of cellular stress in lung disease
General audience summary:
Proteins must be folded properly to function. If this becomes defective, cells experience stress and respond by clearing away these misfolded proteins for destruction. We are investigating how the response to this form of cellular stress is important in lung health and disease. Current projects in our group address a variety of lung diseases including: altered endoplasmic reticulum function in alpha1-antitrypsin deficiency; multiomics analysis of new models of mesothelioma; and the role of GCN2 signalling in pulmonary hypertension.
Strategic CIMR themes: Protein Folding and Quality Control, Organelle Biology, Rare Genetic Diseases
Funding: Medical Research Council (MRC), Asthma + Lung UK, Alpha1-Foundation, June Hancock Mesothelioma Research Fund, LifeArc
Research Group members:
Elaine Soon, Madeline Martinez-Mar, Joe Chambers, Lily Wu, Vera Khodzhaeva, Jose Antonio Valer, Jessy Zhu, Anne Frances
Biography
Stefan studied medicine at the University of Cambridge as part of its MB/PhD Programme. After medical posts in Cambridge, London and Edinburgh, he undertook post-doctoral training in New York funded by the Wellcome Trust and as an MRC Clinician Scientist Fellow back in Cambridge. He established his own group in CIMR as an MRC Senior Clinical Research Fellow in 2012. He is now Professor of Respiratory Science at the University of Cambridge and an Honorary Consultant Respiratory Physician at Addenbrooke’s and Royal Papworth Hospitals. His laboratory research focuses on the role of stress signalling in lung disease. His clinical research focuses on pleural medicine, especially the genetics of pneumothorax. He is Director of the University of Cambridge MB/PhD Programme.
Research
The role of endoplasmic reticulum stress in disease
Studying the consequences of protein misfolding in the endoplasmic reticulum (ER), termed ER stress, particularly on cell growth and survival.
Proteins destined for secretion or for insertion into the cell membrane are first folded within the endoplasmic reticulum. The process of protein folding can become defective in many disease states such as hypoxia, malignancy and some forms of diabetes. When the level of misfolded proteins within the endoplasmic reticulum increases, the cell is said to experience ‘endoplasmic reticulum stress’.
We wish to understand the cellular consequences of endoplasmic reticulum stress, in particular its effects on tissue growth and cell survival. In doing so, we hope to identify targets for the development of novel therapies. During endoplasmic reticulum stress, protein biosynthesis is initially attenuated through phosphorylation of the translation initiation factor eIF2α by the kinase PERK. Subsequent dephosphorylation of eIF2α following the induction of the phosphatase PPP1R15a (GADD34) restores protein translation. We previously discovered that this recovery of translation can contribute to the toxic effects of endoplasmic reticulum stress. This raises the exciting possibility that modulation of eIF2α phosphorylation may provide a useful target for the development of novel drugs to protect tissues from cell death.
Publications
Key Publications
- Brzozowska N, YD Wu, Khodzhaeva V, Griffiths W, Duckworth A, Jung H, Coorens THH, Hooks Y, Chambers JE*, Campbell PJ*, Marciniak SJ*, Hoare M* (2025) Convergent evolution of somatic escape variants in SERPINA1 in the liver in alpha-1 anti-trypsin deficiency. Nature Genetics 57(4):875-883. doi: 10.1038/s41588-025-02125-1. *joint senior. PMID: 40065168 *joint senior
- Yngvadottir B, Richman L, Andreou Avgi, Woodley J, Luharia A, Lim D, Genes & Health Research Team, Maher ER, and Marciniak SJ(2025). Inherited predisposition to pneumothorax: Estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts. Thorax 80(8):553-555. doi:10.1136/thorax-2024-221738. doi: 10.1136/thorax-2024-221738. PMID: 40210444
- Obacz J, Antonio Valer J, Nibhani R, Adams TS, Schupp JC, Veale N, Lewis-Wade A, Flint J, Hogan J, Aresu G, Coonar AS, Peryt A, Biffi G, Kaminski N, Francies H, Rassl DM, Garnett MJ, Rintoul RC, Marciniak SJ (2024). Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma. Eur Respir J 63: 2300143 [DOI: 10.1183/13993003.00143-2023]. PMID: 38212075
- Chambers JE, Zubkov N, Kubánková M, Nixon-Abell J, Mela I, Abreu S, Schwiening M, Lavarda G, López-Duarte I, Dickens JA, Torres T., Kaminski CF, Holt LJ, Avezov E., Huntington JA, St George Hyslop P, Kuimova MK, Marciniak SJ. (2022). Z-⍺1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state. Science Advances 8:eabm2094. doi: 10.1126/sciadv.abm2094. PMID: 35394846.
- Dickens JA, Rutherford E, Abreu S, Chambers JE, Ellis M, van Schadewijk A, Hiemstra P, Marciniak SJ (2022). Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant. Eur Respir J. 59: 2100267; doi: 10.1183/13993003.00267-2021. PMID: 34049951
- Marciniak SJ, Chambers JE, Ron D (2022). Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov. 21: 115-140. doi: 10.1038/s41573-021-00320-3. PMID: 34702991
- Horsley A, Brightling C, Davies J, Djukanovic R, Heaney LG, Hussell T, Marciniak SJ, McGarvey L, Porter JC, Wilkinson T, Ho L-P, on behalf of the NIHR Respiratory Translational Research Collaboration network (2022). Early-phase clinical trials in a pandemic: learning from the response to COVID-19. Lancet Respir Med. 10(7):625-627. doi: 10.1016/S2213-2600(22)00062-5. PMID: 35709826
- Horsley A, Pearmain L, Knight S, Schindler N, Wang R, Bennett M, Robey RC, Davies JC, Djukanovic R, Heaney LG, Hussell T, Marciniak SJ, McGarvey L, Porter JC, Wilkinson T, Brightling C, Ho L-P (2022). Large scale clinical trials - lessons from the COVID-19 pandemic. BMJ Open Respiratory Research 2022;9:e001226. doi: 10.1136/bmjresp-2022-001226 PMID: 35701071
- PHOSP-COVID Collaborative Group#. (2022) Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. Lancet Respir Med. 10:761-775. doi: 10.1016/S2213-2600(22)00127-8. PMID: 35472304. #Includes Marciniak S
- Jordon L, Gore R, Rusk R, Knox-Brown B, Marciniak SJ (2022). The role of impulse oscillometry in the management of asthma when forced expiratory manoeuvres are contraindicated: case series and literature review. J Asthma 59:1577-1583. doi: 10.1080/02770903.2021.1941088. PMID: 34112043
- Chambers JE, Zubkov N, Kubánková M, Nixon-Abell J, Mela I, Abreu S, Schwiening M, Lavarda G, López-Duarte I, Dickens JA, Torres T., Kaminski CF, Holt LJ, Avezov E., Huntington JA, St George Hyslop P, Kuimova MK, Marciniak SJ. (2022). Z-⍺1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state. Science Advances 8:eabm2094. doi: 10.1126/sciadv.abm2094. PMID: 35394846.
- Dickens JA, Rutherford E, Abreu S, Chambers JE, Ellis M, van Schadewijk A, Hiemstra P, Marciniak SJ (2022). Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant. Eur Respir J. 59: 2100267; doi: 10.1183/13993003.00267-2021. PMID: 34049951
- Marciniak SJ, Chambers JE, Ron D (2022). Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov. 21: 115-140. doi: 10.1038/s41573-021-00320-3. PMID: 34702991
- Schwiening M, Swietlik E, Pandya D, Burling K, Barker P, Feng O, Treacy C, Abreu S, Wort S, Pepke-Zaba J, Gräf S, Marciniak SJ, Morrell N, Soon E (2022). Different cytokine patterns in BMPR2-mutation positive patients and pulmonary arterial hypertension patients without mutations and their influence on survival. Chest. 161(6):1651-1656. doi: 10.1016/j.chest.2022.01.019. Epub 2022 Jan 19. PMID: 35063447
- Woodford MR, Andreou A, Baba M, van de Beek I, Malta CD, Glykofridis I, Grimes H, Henske EP, Iliopoulos O, Kurihara M, Lazor R, Linehan WM, Matsumoto K, Marciniak SJ, Namba Y, Pause A, Rajan N, Ray A, Schmidt LS, Shi W, Steinlein OK, Thierauf J, Zoncu R, Webb A, Mollapour M. (2022) Seventh BHD international symposium: recent scientific and clinical advancement. Oncotarget. 2022 13:173-181. doi: 10.18632/oncotarget.28176. eCollection 2022. PMID: 35070081
- Grimes HL, Holden S, Babar J, Karia S, Wetscherek MTA, Barker A, Herre J, Knolle M, Maher ER, Genomics England Research Consortium and Marciniak SJ (2022). Combining clinical, radiological and genetic approaches to pneumothorax management. Thorax. 77(2):196-198. doi: thoraxjnl-2021-217210. PMID: 34145047
- Girish M, Pharoah PD, Marciniak SJ (2022). Meta-analysis of the association between emphysematous change on thoracic computerised tomography scan and recurrent pneumothorax. QJM 115:215-221. doi: 10.1093/qjmed/hcab020. PMID: 33538832
- Kardaman N, Nizami M, Marciniak S, Hogan J, Aresu G (2022). Catamenial pneumothorax. Ann R Coll Surg Engl. 104(4):e109-e112. doi: 10.1308/rcsann.2021.0164. PMID: 34825583
- Foo CT, Pulimood T, Knolle M, Marciniak SJ, Herre J (2021). Ambulatory thoracoscopic pleurodesis combined with indwelling pleural catheter in malignant pleural effusion. Front Surg. 25;8:738719. doi: 10.3389/fsurg.2021.738719. PMID: 34760917
- Matsumoto K, Lim D, Pharoah P, Maher E, Marciniak SJ (2021). A systematic review assessing the existence of pneumothorax-only mutations of FLCN. Implications for lifelong surveillance of renal tumours. Eur J Hum Genet 29(11):1595-1600. doi: 10.1038/s41431-021-00921-x. PMID: 34267338
- Evans RA, McAuley H, Harrison EM, Shikotra A, Singapuri A, Sereno M, Elneima O, Docherty AB, Lone NI, Leavy OC, Daines L, Baillie JK, Brown JS, Chalder T, De Soyza A, Diar Bakerly N, Easom N, Geddes JR, Greening NJ, Hart N, Heaney LG, Heller S, Howard L, Hurst JR, Jacob J, Jenkins RG, Jolley C, Kerr S, Kon OM, Lewis K, Lord JM, McCann GP, Neubauer S, Openshaw PJM, Parekh D, Pfeffer P, Rahman NM, Raman B, Richardson M, Rowland M, Semple MG, Shah AM, Singh SJ, Sheikh A, Thomas D, Toshner M, Chalmers JD, Ho LP, Horsley A, Marks M, Poinasamy K, Wain LV, Brightling CE; PHOSP-COVID Collaborative Group#. (2021). Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study. Lancet Respir Med. 9(11):1275-1287. doi: 10.1016/S2213-2600(21)00383-0. #Includes Marciniak S. PMID: 34627560
- Sutherland WJ, Taylor NG, Aldridge DC, Martin P, Rhodes C, Shackelford G, Beard S, Belfield H, Bladon AJ, Brick C, Christie AP, Dobson AP, Downey H, Hood ASC, Hua F, Hughes AC, Jarvis RM, MacFarlane D, Morgan WH, Mupepele A-C, Marciniak SJ, Nelson C, hÉigeartaigh SO, Rojas CR, Sainsbury KA, Smith RK, Sundaram LS, Thornton A, Watkins J, White TB, Willott K & Petrovan SO (2021). A solution scan of societal options to reduce transmission and spread of respiratory viruses: SARS-CoV-2 as a case study. J Biosaf Biosecur 3(2):84-90 doi: 10.1016/j.jobb.2021.08.003. PMID: 34541465
- Smolinska A, Jessop DS, Pappan KL, De Saedeleer A, Kang A, Martin A, Allsworth M, Tyson C, Bos M, Clancy M, Morel M, Cooke T, Dymond T, Harris C, Galloway J, Bresser P, Dijkstra N, Jagesar V, Savelkoul P, Beuken EVH, Nix WVH, Louis R, Delvaux M, Calmes D, Ernst B, Pollini S, Peired A, Guiot J, Tomassetti S, Budding AE, McCaughan F, Marciniak SJ, van der Schee MP (2021). SARS-CoV-2 viral load is lower on face mask filters worn by COVID-19 patients than on nasopharyngeal swabs. Sci Rep 11(1):13476 doi: 10.1038/s41598-021-92665-3. PMID: 34188082
- Obacz J, Yung H, Shamseddin M, Linnane E, Liu X, Azad A, Rassl D, Fairen-Jimenez D, Rintoul RC, Nikolic M, Marciniak SJ (2021). Biological basis for novel mesothelioma therapies. Br J Cancer. 125(8):1039-1055. doi: 10.1038/s41416-021-01462-2. PMID: 34226685
- Marciniak SJ, Farrell J, Rostron A, Smith I, Openshaw PJM, Baillie JK, Docherty A, Semple MG (2021). COVID-19 Pneumothorax in the United Kingdom: a prospective observational study using the ISARIC WHO clinical characterisation protocol. Eur Respir J. 58:2100929 doi: 10.1183/13993003.00929-2021. PMID: 34083401
- Ordonez A, Harding HP, Marciniak SJ, Ron D (2021). Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers. Cell Rep 35(7):109144. doi: 10.1016/j.celrep.2021.109144. PMID: 34010647
- Shamseddin M, Obacz J, Garnett MJ, Rintoul RC, Francies HE, Marciniak SJ (2021). The use of preclinical models for malignant pleural mesothelioma. Thorax 76(11):1154-1162. doi: 10.1136/thoraxjnl-2020-216602. PMID: 33692175
- Lomas DA, Irving JA, Arico-Muendel C, Belyanskaya S, Brewster A, Brown M, Chung C, Dave H, Denis A, Dodic N, Dossang A, Eddershaw P, Klimaszewska D, Haq I, Holmes DS, Hutchinson JP, Jagger A, Jakhria T, Jigorel E, Liddle J, Lind K, Marciniak SJ, Messer J, Neu M, Olszewski A, Ordonez A, Ronzoni R, Rowedder J, Rüdiger M, Skinner S, Smith KJ, Terry R, Trottet L, Uings I, Wilson S, Zhu Z and Pearce AC. (2021). Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin. EMBO Mol Med e13167 https://doi.org/10.15252/emmm.202013167. PMID: 33512066
- Mann ER, Menon M, Knight SB, Konkel JE, Jagger C, Shaw TN, Krishnan S, Rattray M, Ustianowski A, Bakerly ND, Dark P, Lord G, Simpson A, Felton T, Ho L-P, NIHR Respiratory TRC#, Feldmann M, CIRCO, Grainger JR, Hussell T (2020). Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci. Immunol. 5, eabd6197. doi: 10.1126/sciimmunol.abd6197. #Includes Marciniak S
Teaching and Supervisions
- Director of the University of Cambridge MB/PhD Programme -- https://www.medschl.cam.ac.uk/education/courses/mbphd/
- Director of 1A Medical Studies in Clinical Medicine – St Catharine’s College
Current PhD students
- Lily Wu
- Jessy Zhu
- Niki Veale
Previous Graudate students
- PhD Heike Kroger
- PhD Elke Malzer
- PhD Sally Thomas
- PhD Jenny Dickens
- PhD Hanna Clarke
- PhD Vruti Patel
- PhD Caia Dominicus
- Eimear Rutherford
- Haoyang Ying
- Nikita Zubkov
- Max Schwiening
- MPhil Marie-Louise Daly
- MPhil Nicolas Piton
- MPhil Elizabeth Liniker
- MPhil Nikita Zhubkov
- MPhil Ahmad Hilder
- MPhil Alexandra Ekvik
- MPhil Qingyue “Sherry” Gao
- MPhil Courtney Townend
Other Professional Activities
- Professor of Respiratory Science, University of Cambridge
- Directorate Research Lead, Addenbrooke’s Hospital: Allergy, Infection & Inflammation
- Honorary Consultant Respiratory Physician, Addenbooke’s Hospital
- Honorary Consultant Respiratory Physician, Royal Papworth Hospital
- MB/PhD Programme Director, University of Cambridge
- NIHR Translational Research Collaboration for Inflammatory Respiratory Diseases Steering Committee Meeting, joint lead for Pleural Medicine
- MKMRF/BLF Mesobank UK Mesothelioma Tissue Bank steering committee
- Alpha-1 Foundation (USA), Grants Advisory Committee (chair)
- Mesothelioma UK, Research and Science Committee (chair)
- LifeArc Rare Respiratory Disease Centre, co-lead
