2. Academic Validation
  3. Early fibrotic niches establish tumour-permissive microenvironments

Early fibrotic niches establish tumour-permissive microenvironments

  • Nature. 2026 May;653(8113):254-264. doi: 10.1038/s41586-026-10399-6.
Erik C Cardoso # 1 2,  Hyeyoung Lee # 3,  Frances J England 1,  Hyunjin Cho 3,  Robin Lu 2,  Sagar S Varankar 1,  Moo Suk Park 4,  Natasha Rekhtman 5,  Bon-Kyoung Koo 6,  Benjamin D Simons 1 7 8,  Jinwook Choi 9 10,  Joo-Hyeon Lee 11 12
Affiliations

Affiliations

  • 1 Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
  • 2 Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Department of Life Sciences, Integrated Institute of Biomedical Research, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
  • 4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 5 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Center for Genome Engineering, Institute for Basic Science, Daejeon, Republic of Korea.
  • 7 Gurdon Institute, University of Cambridge, Cambridge, UK.
  • 8 Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Science, University of Cambridge, Cambridge, UK.
  • 9 Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. [email protected].
  • 10 Department of Life Sciences, Integrated Institute of Biomedical Research, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. [email protected].
  • 11 Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. [email protected].
  • 12 Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 42020743 DOI: 10.1038/s41586-026-10399-6
Abstract

Pathologic transformation represents a critical yet poorly defined window during which mutant epithelial stem cells actively construct the microenvironment that enables tumour initiation1,2. Here using integrated single-cell, spatial and functional analyses, we define the earliest multicellular events that licence this transition following oncogenic activation in the lung. KrasG12D-mutant alveolar type II cells rapidly adopt regenerative-like states that act as signalling hubs, orchestrating coordinated stromal and immune reprogramming while enhancing epithelial plasticity. Through secretion of Amphiregulin, mutant epithelial cells activate EGFR signalling in adjacent fibroblasts, inducing a fibrotic, injury-like programme. Reprogrammed fibroblasts, in turn, expand and reprogramme alveolar macrophages, amplifying inflammatory signalling and reinforcing epithelial plasticity. These reciprocal interactions establish a self-sustaining epithelial-stromal-immune circuit that generates a tumour-permissive niche before malignant outgrowth. Disruption of the amphiregulin-EGFR axis prevents early niche formation and abrogates tumour initiation. Conservation of this programme in KRASG12D-inducible human alveolar organoids and early-stage lung adenocarcinoma tissues identifies epithelial-microenvironment communication as a therapeutically actionable vulnerability and suggests that intercepting niche formation may prevent progression to treatment-resistant disease.

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