Abstract
Lung cancer leads to a series of physiological abnormalities. The remodeling of extracellular matrix (especially elastin and collagen fibers) has been drawing increasing attention as it is suggested to be a hallmark of tumorigenesis. However, the interaction between these crucial matrix components, together with their relationship to mechanical changes, remains poorly understood. Here, we develop a quantitative multiphoton microscopy system to elucidate the relationship between tissue stiffening and elastin-collagen interplay in lung cancer. Based on label-free images of both fibers, we establish a metric termed resemblance metric (RM) to characterize their interaction by quantifying the similarity of their morpho-structural distributions. Specifically, RM is found to increase with lung tumorigenesis, and exhibits superior sensitivity in identifying human lung cancer through ex vivo quantitative imaging. Nanoindentation results suggest a strong correlation between tissue stiffness and inter-channel interaction, notably greater than that between stiffness and any individual morpho-structural feature of either fiber type. Finally, the translational potential of RM-based imaging is demonstrated through tumor boundary identification via in vivo imaging within a mouse model harboring human lung cancer.
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Data availability
All data supporting the findings of this study are available within the paper and its Supplementary Information. The source data that make up all graphs in the paper are shown in Supplementary Data 1. The source data for animal tumor experiments are provided in Supplementary Data 2. Any further data that support the findings of this study are available from the corresponding authors upon reasonable request.
Code availability
Custom MATLAB (R2023a) source code including illustrative example data for the calculation of RM has been deposited on GitHub (https://github.com/dukeotter/Resemblance_Index_Demo_Availability), and on the Zenodo platform65.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (62275232 to Z.L., 62375104 to S.Z., 32371411 to X.W., and 62575254 to Z.D.) and the Natural Science Foundation of Zhejiang Province (LZ25F050007 to Z.L.).
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Z.L., S.Z., X.W., Z.D., K.S., and C.W. conceived the idea. C.W., S.Q., L.Z., J.M., and R.J. performed the experiments and imaging. C.W., S.Q., J.M., L.Z., L.C., and B.N. conducted the simulation experiments. C.W., S.Q., L.Z., L.C. and Z.L. performed data analysis with conceptual support from all authors. X.W., W.L., and C.W. conducted the nanoindentation experiments. C.W., Z.L., and S.Q. drafted the main manuscript, with suggestions from all authors. All authors discussed the results and commented on the manuscript.
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Wang, C., Qian, S., Li, W. et al. Interpreting tissue stiffening with lung tumorigenesis by imaging architectural resembling of extracellular matrix components. Commun Biol (2026). https://doi.org/10.1038/s42003-026-10004-6
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DOI: https://doi.org/10.1038/s42003-026-10004-6
