Fig 1.
Early lung adenocarcinoma (LUAD) is characterized by alveolar filling.
Lung tissue slides stained with Masson’s Trichrome to distinguish cells from connective tissue. Cell nuclei are dark purple, cytoplasm light red, and collagen blue. A. Alveolar architecture of normal lung from Kras+/+; Trp5f/f mice. B. Tumor from KrasLSL-G12D/+; Trp53f/f mice 10 weeks and C. 25 weeks after intra-tracheal inoculation with SPC-Cre. Images are representative of lung tissue from 3 Kras+/+ mice or tumors from 3 mice KrasLSL-G12D/+ mice at each time point.
Fig 2.
Implementation of a geometric tissue-scale constitutive model of lung cancer.
A. Lung model, in which alveoli are represented as shell elements organized in a randomized hexagonal lattice. Model is 9,885 μm x 10,000 μm x 30 μm. B. Zoomed-in view of tumor and adjacent matrix under 0% and 50% globally applied stretch in x and y, displacement in z is fixed. C. Discretization of the lung model. Alveoli are represented by shell elements. The tumor is discretized using tetrahedral elements with a surrounding basement membrane of triangular elements.
Table 1.
Reported Mechanical Properties of Lung Tissuea.
Fig 3.
Lung tumors amplify strain in surrounding alveoli during inspiration.
Strain colormaps after 20% stretch. A. Normal lung, B. lung with 2 kPa early tumor, and C. lung with a 20 kPa late tumor. Dotted line represents the location on the normal mesh of the tumor boundary. Colormap is % Green-Lagrange shell strain. D-F. Strain ratios in each model. Inset in D. is a schematic of the measured alveolar wall segments in which the dark-to-light colors represent the distance from the tumor edge. Boxes are 25th percentile to 75th percentile with the median and maximum and minimum values labeled. In D., for all comparisons of strain ratio in the normal lung, p > 0.999. Distribution includes all alveolar wall segments at each indicated distance.
Table 2.
Reported Mechanical Properties of Tumor Tissue.
Fig 4.
Early lung tumors harbor strain amplification at the tumor edge.
Colormaps of strain after 20% stretch within the tumor in tissue with A. 2 kPa tumor and B. 20 kPa tumor. Colormaps display strain only on the tumor surface. C. Element strain ratio as a function of distance from the tumor center of mass, 2 kPa tumor at 20% applied stretch. Elements with strain ratio > 1 (grey line) were considered amplified. D. Distribution of the strain ratio in amplified elements (n) as a function of applied stretch, 2 kPa tumor. n = 155 at 5% stretch, 91 at 20% stretch, and 99 at 50% stretch, out of 11,829 elements. E. Percent of elements with a strain ratio >1, dependent on the tumor modulus value (E).
Fig 5.
Thick alveolar walls around the tumor displaces strain amplification further into the lung.
A. Early tumor in the mouse LUAD model (Masson Trichrome, original magnification 40x). B. Quantification of the alveolar wall width around mouse tumors within 3 alveoli from the tumor edge (adjacent) and > 1 mm away from the tumor. Measurements are pooled from 3 tumors in 2 mice. C. Human T1 LUAD (H&E, magnification 10x) D. Quantification of human alveolar wall width from 5 cases of T1 LUAD with a distinct tumor boundary and 2 samples of normal tissue >4 cm away from any tumor. E. Diagrams of tumor models in which adjacent alveoli have walls with original thickness of 10 μm or thickened walls of 30 μm. Thickened walls are indicated in red. F. Strain colormap around a 2 kPa tumor with thickened alveolar walls, 20% stretch. G. Strain ratio at 20% applied stretch between the baseline (10 μm) and thickened (30 μm) condition. At each alveolar distance from the tumor, p > 0.999 for 10 μm vs 30 μm comparisons.
Fig 6.
Strain-mediated alveolar wall thickening produces tracks that emulate ECM remodeling in human LUAD.
A. Simulated thickening in alveolar wall elements that experience 28% Lagrange strain at 20% applied stretch for 5 iterations. Alveolar walls thickened to 30 μm are represented in red. B. Tenascin-C staining of a normal human lung, representative of n = 2. C. Tenascin-C staining at the edge of a T2 human tumor, representative of n = 6 T1 and T2 tumors. Dotted line shows the tumor edge (DAB with hematoxylin, 10x magnification). D. Inset from C. shows tracks of thick, Tenascin-C-stained alveolar walls that extend out from the tumor (40x magnification). Red lines mark the tracks of Tenascin-C. E. Serial section from C. (H&E, 40x magnification). Arrowheads indicate tumor cells with enlarged nuclei residing on thickened tracks.