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. 2022 Oct;33(10):1085-1088.
doi: 10.1016/j.annonc.2022.06.005. Epub 2022 Jun 25.

Single cell heterogeneity and evolution of breast cancer bone metastasis and organoids reveals therapeutic targets for precision medicine

K Ding  1 , F Chen  2 , N Priedigkeit  3 , D D Brown  4 , K Weiss  5 , R Watters  6 , K M Levine  7 , T Heim  5 , W Li  8 , J Hooda  9 , P C Lucas  10 , J M Atkinson  11 , S Oesterreich  12 , A V Lee  13
Affiliations

Single cell heterogeneity and evolution of breast cancer bone metastasis and organoids reveals therapeutic targets for precision medicine

K Ding et al. Ann Oncol. 2022 Oct.
No abstract available

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Figures

Figure 1.
Figure 1.. Histological and multiomics profiling of paired primary ILC and bilateral BoMs, and target evaluation with associated BoM PDOs.
(A) Hematoxylin and eosin (H&E) staining, and immunohistochemical staining of E-cad/p120 and ER of primary tumor, left pelvis metastasis (BoML) and right tibia metastasis (BoMR). E-cad is stained brown, and p120 is stained pink. (B) Comparison of exonic somatic substitutions identified in BoMs with primary tumor, with allele frequency cutoff ≥ 0.1. (C) Genes with the top 3% fold change gains (top panel) and losses (bottom panel) in either BoM compared to the primary tumor. Labeled genes are clinical actionable genes based upon DGIdb. Arrows indicate frequently upregulated (red) and downregulated (blue) genes in breast cancer BoMs reported by Priedigkeit N et.al. (D) GSVA analysis of Hallmark gene sets from MsigDB in the primary tumor and BoMs. Pathways with GSVA score difference between the primary tumor and either BoM more than 0.6 are shown. (E) UMAP of cell clusters identified by scRNAseq of BoML/R, with cell types assigned based on the expression of canonical markers and SingleR automatic cell type assignment. (F) UMAP of subpopulations of epithelial cells from BoML/R with top enriched pathways of each cluster annotated. (G) Comparison of relative abundance of epithelial subpopulations between PDO and paired BoM using FindTransferAnchors function of Seurat. Cluster numbers in Figure G correspond to cluster numbers in Figure F. (H-I) Dose response curves of PDOs to Alpelisib (H) and Talazoparib (I). IC50 was calculated using a nonlinear regression model with variable slopes. MCF7 with PI3K (E545K) mutation and PDO86 with wild type BRCA1 were used as controls. Data is shown as mean −/+ SD. n=3 for each experiment. (J) Relative growth of PDOL murine xenografts under the treatment of vehicle (Veh; 0.5% carboxymethylcellulose) or 50mg/kg/day Alpelisib by daily gavage for 4 weeks. Treatment was initiated when tumors reached ~200mm3 with 7 mice in each treatment arm. Tumor volume was measured twice a week with caliper. Dashed lines are the relative growth curves of individual tumor. Solid lines are the average relative growth of each group, shown as mean −/+ SD. p value of tumor growth differences between the Vehicle and Alpelisib groups was calculated by two-way ANOVA. ****p<0.0001. E-cad: E-cadherin, ER: Estrogen receptor, BoM: bone metastasis, PDOs: patient-derived organoids, PDOL: patient-derived organoid left (bone metastases).
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