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Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression
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Aberrant basal cell clonal dynamics shape early lung carcinogenesis.

Sandra Gómez-López1, Ahmed S N Alhendi1, Moritz J Przybilla2

  • 1Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.

Science (New York, N.Y.)
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Carcinogen exposure drives lung squamous cell carcinoma (LUSC) precursors through competitive basal cell growth and expansion. These findings reveal how early-stage lung cancer develops from mutated clones across the bronchial tree.

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Area of Science:

  • Pulmonary Medicine
  • Cancer Biology
  • Cellular Dynamics

Background:

  • Preinvasive squamous lung lesions precede lung squamous cell carcinoma (LUSC).
  • The cellular mechanisms driving the formation of these precursor lesions remain largely unknown.
  • Understanding these early events is crucial for developing effective lung cancer prevention and early detection strategies.

Purpose of the Study:

  • To investigate the cellular events and clonal dynamics underlying the formation of preinvasive squamous lung lesions.
  • To identify the key cellular processes that lead to the development of lung squamous cell carcinoma (LUSC).
  • To explore the concept of field cancerization in the context of lung squamous lesions.

Main Methods:

  • Utilized a carcinogen-induced mouse model for lung squamous cell carcinoma (LUSC) development.
  • Analyzed basal cell competition, clonal expansion, and mobilization along airways.
  • Performed multisite sequencing in human patients to confirm findings in distinct airway regions.

Main Results:

  • Carcinogen exposure induced non-neutral competition among basal cells, leading to aberrant clonal expansions.
  • Basal cells mobilized along airways, contributing to lesion formation.
  • Preinvasive lesions originated from a few dominant, highly mutated clones affecting large areas of the bronchial tree.
  • Human patient data confirmed clonally related preinvasive lesions across different airway locations.

Conclusions:

  • A significant transition in basal cell clonal dynamics and cell fate occurs during preinvasive lesion development.
  • These cellular changes are key drivers of field cancerization in the lung.
  • The study provides critical insights into the early pathogenesis of lung squamous cell carcinoma (LUSC).