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Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer

Author

Listed:
  • Christopher J. Hanley

    (University of Southampton
    Cancer Research UK and NIHR Southampton Experimental Cancer Medicine Centre)

  • Sara Waise

    (University of Southampton)

  • Matthew J. Ellis

    (University of Southampton)

  • Maria A. Lopez

    (University Hospital Southampton NHS Foundation Trust)

  • Wai Y. Pun

    (University Hospital Southampton NHS Foundation Trust)

  • Julian Taylor

    (University Hospital Southampton NHS Foundation Trust)

  • Rachel Parker

    (University of Southampton)

  • Lucy M. Kimbley

    (University of Southampton)

  • Serena J. Chee

    (University of Southampton
    University of Liverpool)

  • Emily C. Shaw

    (University Hospital Southampton NHS Foundation Trust)

  • Jonathan West

    (University of Southampton
    University of Southampton)

  • Aiman Alzetani

    (University Hospital Southampton NHS Foundation Trust)

  • Edwin Woo

    (University Hospital Southampton NHS Foundation Trust)

  • Christian H. Ottensmeier

    (University of Southampton
    Cancer Research UK and NIHR Southampton Experimental Cancer Medicine Centre
    University of Liverpool)

  • Matthew J. J. Rose-Zerilli

    (University of Southampton
    University of Southampton)

  • Gareth J. Thomas

    (University of Southampton
    Cancer Research UK and NIHR Southampton Experimental Cancer Medicine Centre
    University Hospital Southampton NHS Foundation Trust)

Abstract

Fibroblasts are poorly characterised cells that variably impact tumour progression. Here, we use single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry (CIBERSORTx) to identify and characterise three major fibroblast subpopulations in human non-small cell lung cancer: adventitial, alveolar and myofibroblasts. Alveolar and adventitial fibroblasts (enriched in control tissue samples) localise to discrete spatial niches in histologically normal lung tissue and indicate improved overall survival rates when present in lung adenocarcinomas (LUAD). Trajectory inference identifies three phases of control tissue fibroblast activation, leading to myofibroblast enrichment in tumour samples: initial upregulation of inflammatory cytokines, followed by stress-response signalling and ultimately increased expression of fibrillar collagens. Myofibroblasts correlate with poor overall survival rates in LUAD, associated with loss of epithelial differentiation, TP53 mutations, proximal molecular subtypes and myeloid cell recruitment. In squamous carcinomas myofibroblasts were not prognostic despite being transcriptomically equivalent. These findings have important implications for developing fibroblast-targeting strategies for cancer therapy.

Suggested Citation

  • Christopher J. Hanley & Sara Waise & Matthew J. Ellis & Maria A. Lopez & Wai Y. Pun & Julian Taylor & Rachel Parker & Lucy M. Kimbley & Serena J. Chee & Emily C. Shaw & Jonathan West & Aiman Alzetani , 2023. "Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35832-6
    DOI: 10.1038/s41467-023-35832-6
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