Fig. 4: CTHRC1+ fibroblasts are located at the leading edge from nontumor to tumor regions.
a, Left, hematoxylin and eosin staining of a tissue section from participant HCC-IL. Middle, distribution of normal, tumor and transition regions in participant HCC-1L (images reproduced with permission from ref. 39, AAAS). Right, spatial feature plot of the eFibro_CTHRC1 signature score; scale bars, 100 μm. b, Correlation between the eFibro_CTHRC1 signature score and the distance between spots and malignant cells in all ST samples. Correlations were calculated using Pearson correlation coefficients. Resulting P values were adjusted for multiple comparisons via the BH method. The significant negative correlation represents the CTHRC1+ fibroblasts surrounding malignant cells in the ST samples; PLC, pulmonary lymphangitic carcinomatosis. c, Scatter plots showing the correlation between the distance to malignant cells (x axis) and the signature score of eFibro_CTHRC1 (y axis) in tissue sections. The correlation was calculated using Pearson correlation coefficients. The color represents the proportion of fibroblasts in each spot. The error band indicates the 95% confidence interval, which is calculated based on the standard error using the normal distribution. The center measure of the smooth line corresponds to the predicted values from the linear regression model. d, IHC staining to validate the distribution of eFibro_CTHRC1 cells; scale bars, 100 μm; PanCK, pan-cytokeratin. e, Box plot showing the correlation between inferred inducers of CTHRC1+ fibroblasts and the CTHRC1+ fibroblast signature score. The red box represents data calculated from 62 ST samples, whereas the green box is derived from 9,460 samples across 23 cancer types in the TCGA project. The bottom of each box indicates Q1, and the top represents Q3. The height of the box reflects the IQR, and the horizontal line inside the box indicates the median. The whiskers extend to the positions of Q1 – 1.5 × IQR and Q3 + 1.5 × IQR. f, Comparison of the relative intensity (each row shared a color scale, whereas different rows did not) of immune cell-type scores between the normal and tumor regions of ST slides, focusing on the ST samples with eFibro_CTHRC1 cells surrounding tumor cells. g, Bubble heat map showing the interaction strength of gene pairs between fibroblasts and immune cells. Colors in the bubble plot are proportional to the communication probability. Significant interactions are identified on the basis of a statistical test that randomly permutes the group labels of cells and then recalculates the interaction probability. h, Inferred LGALS9 and CD44 interaction between CD4+ T cells and fibroblasts; Tfh, follicular helper T cell.
