Aberrant basal cell clonal dynamics shape early lung carcinogenesis.
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| Title: | Aberrant basal cell clonal dynamics shape early lung carcinogenesis. |
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| Authors: | Gómez-López, Sandra, Alhendi, Ahmed S. N., Przybilla, Moritz J., Bordeu, Ignacio, Whiteman, Zoe E., Butler, Timothy, Rouhani, Maral J., Kalinke, Lukas, Uddin, Imran, Otter, Kate E. J., Chandrasekharan, Deepak P., Lebrusant-Fernandez, Marta, Shurr, Abigail Y. L., Durrenberger, Pascal F., Moore, David A., Falzon, Mary, Reading, James L., Martincorena, Iñigo, Simons, Benjamin D., Campbell, Peter J. |
| Source: | Science. 6/12/2025, Vol. 388 Issue 6752, p1-14. 14p. |
| Subjects: | Squamous cell carcinoma, Lung cancer, Carcinogens, Carcinogenesis, Genetic mutation |
| Abstract: | Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we found that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions developed from a few highly mutated clones that dominate most of the bronchial tree. Multisite sequencing in human patients confirmed the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung. Editor's summary: Despite recent progress in promoting smoking cessation, tobacco-induced lung cancer remains a common and deadly disease. These cancers usually show up many years or decades after the initial exposure to tobacco, suggesting that detailed insights into premalignant changes in the lungs, known as field cancerization, may help to identify at-risk patients and approaches for early intervention. To study this biological phenomenon, Gómez-López et al. performed detailed analysis on lung cells from carcinogen-exposed mice and from humans with or without a history of smoking. The findings shed light on carcinogen-induced changes in cell evolution and competition in the lung and help to identify the cells that give rise to preinvasive lesions and the mechanisms involved. —Yevgeniya Nusinovich INTRODUCTION: Lung cancer remains the leading cause of cancer-related deaths worldwide. Lung squamous cell carcinoma is the second most common subtype and develops in a stepwise process from increasingly disorganized preinvasive lesions in the bronchial epithelium. The biological mechanisms underlying the transition of the normal epithelium to precancerous states are poorly understood. RATIONALE: The normal tracheobronchial epithelium is maintained by basal cells, which divide to self-renew and to produce differentiated luminal cells. Basal cells naturally accumulate mutations throughout an individual's lifetime. Exposure to mutagens, such as those found in tobacco cigarette smoke, increases not only the mutational burden in basal cells but also the incidence of cancer-associated mutations. We set out to elucidate the cellular processes that lead to the formation of precancerous lesions by tracking basal cell trajectories in a carcinogen-driven mouse model of lung squamous cell cancer and by delineating cell state changes in the normal airway epithelium of current smokers. To better understand the early evolutionary dynamics of lesion precursors, we investigated clonal relationships between spatially separate lesions in the bronchial tree. RESULTS: Using genetic-lineage tracing, we have demonstrated that preinvasive lesions originate from basal cells. In mice, we found that carcinogen exposure results in non-neutral competition between basal cell clones, which eventually drives mutant clone dominance in the bronchial tree. This change in clonal dynamics is associated with a shift in basal cell fate, which has also been identified in the airway of human smokers. This leads to disturbed basal cell homeostasis, an increase of cells in transitional state, and decreased luminal differentiation. In mouse and human, we found clonally related lesions across distinct anatomical sites, suggesting aberrant migration of cancer precursor cells. CONCLUSION: Our work identifies a cell fate shift in airway basal cells as they transition into precancerous states and highlights mutant basal cell clone expansions and aberrant cell migration as key events during the initiation of lung squamous cell carcinogenesis. This provides a conceptual framework for future investigations of the biology of precancerous lesions and may open new avenues for early cancer interception. Disruption of basal cell homeostasis drives early lung carcinogenesis.: Carcinogen exposure leads to cell fate changes in airway basal cells. Subpopulations of mutant basal cells may preferentially expand symmetrically, leading to loss of differentiated luminal cells and mutant cell clonal expansions. Mutant basal cell clones can migrate along the bronchial tree, where they eventually produce preinvasive squamous cell lesions. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we found that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions developed from a few highly mutated clones that dominate most of the bronchial tree. Multisite sequencing in human patients confirmed the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung. Editor's summary: Despite recent progress in promoting smoking cessation, tobacco-induced lung cancer remains a common and deadly disease. These cancers usually show up many years or decades after the initial exposure to tobacco, suggesting that detailed insights into premalignant changes in the lungs, known as field cancerization, may help to identify at-risk patients and approaches for early intervention. To study this biological phenomenon, Gómez-López et al. performed detailed analysis on lung cells from carcinogen-exposed mice and from humans with or without a history of smoking. The findings shed light on carcinogen-induced changes in cell evolution and competition in the lung and help to identify the cells that give rise to preinvasive lesions and the mechanisms involved. —Yevgeniya Nusinovich INTRODUCTION: Lung cancer remains the leading cause of cancer-related deaths worldwide. Lung squamous cell carcinoma is the second most common subtype and develops in a stepwise process from increasingly disorganized preinvasive lesions in the bronchial epithelium. The biological mechanisms underlying the transition of the normal epithelium to precancerous states are poorly understood. RATIONALE: The normal tracheobronchial epithelium is maintained by basal cells, which divide to self-renew and to produce differentiated luminal cells. Basal cells naturally accumulate mutations throughout an individual's lifetime. Exposure to mutagens, such as those found in tobacco cigarette smoke, increases not only the mutational burden in basal cells but also the incidence of cancer-associated mutations. We set out to elucidate the cellular processes that lead to the formation of precancerous lesions by tracking basal cell trajectories in a carcinogen-driven mouse model of lung squamous cell cancer and by delineating cell state changes in the normal airway epithelium of current smokers. To better understand the early evolutionary dynamics of lesion precursors, we investigated clonal relationships between spatially separate lesions in the bronchial tree. RESULTS: Using genetic-lineage tracing, we have demonstrated that preinvasive lesions originate from basal cells. In mice, we found that carcinogen exposure results in non-neutral competition between basal cell clones, which eventually drives mutant clone dominance in the bronchial tree. This change in clonal dynamics is associated with a shift in basal cell fate, which has also been identified in the airway of human smokers. This leads to disturbed basal cell homeostasis, an increase of cells in transitional state, and decreased luminal differentiation. In mouse and human, we found clonally related lesions across distinct anatomical sites, suggesting aberrant migration of cancer precursor cells. CONCLUSION: Our work identifies a cell fate shift in airway basal cells as they transition into precancerous states and highlights mutant basal cell clone expansions and aberrant cell migration as key events during the initiation of lung squamous cell carcinogenesis. This provides a conceptual framework for future investigations of the biology of precancerous lesions and may open new avenues for early cancer interception. Disruption of basal cell homeostasis drives early lung carcinogenesis.: Carcinogen exposure leads to cell fate changes in airway basal cells. Subpopulations of mutant basal cells may preferentially expand symmetrically, leading to loss of differentiated luminal cells and mutant cell clonal expansions. Mutant basal cell clones can migrate along the bronchial tree, where they eventually produce preinvasive squamous cell lesions. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.ads9145 |
