Fig. 5: Morphological intratumor heterogeneity of tumor nuclei indicates cell cycle pathway activity and CDK inhibitor response in HR+breast cancer. | Nature Communications

Fig. 5: Morphological intratumor heterogeneity of tumor nuclei indicates cell cycle pathway activity and CDK inhibitor response in HR+breast cancer.

From: Single-cell morphological and topological atlas reveals the ecosystem diversity of human breast cancer

Fig. 5: Morphological intratumor heterogeneity of tumor nuclei indicates cell cycle pathway activity and CDK inhibitor response in HR+breast cancer.The alternative text for this image may have been generated using AI.

a Calculation of MITH. Created with BioRender.com. b Representative local images of high- and low-MITH tumors. Scale bar: 200 μm. c Correlation between MITH and genetic intratumor heterogeneity. Fitted linear regression line is shown. Two-sided Spearman correlation analysis is performed. d Association between MITH and clinicopathological features. P values are calculated using the two-sided Mann-Whitney U test. e Gene sets enriched in high-MITH samples in HR+ breast cancers revealed by GSEA. Cell cycle-related gene sets are marked in red. The NES and FDR output by GSEA are presented. f Comparison of Ki-67 index and MGPS between high- and low-MITH samples in HR+ breast cancers. P values are calculated using the two-sided Mann-Whitney U test. g Diagram depicting how Cyclin D/CDK4/6 and Cyclin E/CDK2 regulate G1/S phase progression and activate transcription of E2F target genes. h Comparison of phospho-Rb (S807/811) IHC score between high- (n = 164) and low-MITH (n = 163) samples in HR+ breast cancers. Representative images of IHC staining are presented. Scale bar: 100 μm. P value is calculated using the two-sided Mann-Whitney U test. i Heatmap of the mRNA expression of CCND1, CCND2, CCND3, CDK4, CDK6, CCNE1, CCNE2, CDK2, E2F1, E2F2, E2F3 and E2F target signature score in HR+ breast cancers. Their correlation with MITH is indicated by bar plot on the right through two-sided Spearman correlation analysis. ***P < 0.001; *P < 0.05; ns, not significant. j Experiment design to evaluate CDK inhibitor response of PDOs stratified by MITH. Created with BioRender.com. k Relative viability of PDOs treated with 1 μM CDK4/6 inhibitor Abemaciclib and 0.4 μM CDK2/4/6 inhibitor PF-06873600 (High-MITH: n = 12; low-MITH: n = 9). P values are calculated using two-sided Mann–Whitney U test. For Fig. 5d, f, h and k, the center lines of boxplots indicate median values; box limits show upper and lower quartiles; whiskers extend from box limits to the farthest data point within 1.5 × interquartile range; points beyond whiskers are outliers. In Fig. 5e, f, h and k, high- and low-MITH subgroups are defined using the median MITH value (0.8798) of HR+ breast cancers. MITH morphological intratumor heterogeneity, CC correlation coefficient, NES normalized enrichment score, FDR false discovery rate, MGPS multigene proliferation score, IHC immunohistochemistry.

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