Fig. 6. The global view tumor heterogeneity within one intact HCC nodule.

(A) A case of HCC (HCC-5) with a diameter of about 1 cm was divided into four sections (A, B, C, and D sections) to analyze the global spatial heterogeneity. Photo credit: Rui Wu, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China. (B) Distribution of clusters in the tissue space and UMAP space. (C) Fractions of the clusters in each section. (D) Spatial feature plots of six differentially expressed genes on HCC-5. (E) Distribution of the divided sectors and annuluses on the tumor region (top). Each section was equally divided into four sectors (middle). Each annulus area was five spots wide (bottom). (F) Bubble heatmap showing the Spearman correlation between the median of the hallmark pathway activities and the annular orders in the tumor clusters of different sectors. A-1.1 represented cluster 1 in sector A-1. Dot color indicated the correlation values. Dot size indicated the statistical significance. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (G) Spatial distribution of the oxidative phosphorylation pathway activities. (H) Change of oxidative phosphorylation pathway median activities along with the annulus orders from inside to the outside in the D-3.1, D-4.1, B-4.2, and D-1.2 (bottom). The Spearman correlations and statistical significances were labeled. *P < 0.05; **P < 0.01; ***P < 0.001.