Flowchart of CASCAM for congruence quantification and selection.

Tumor and cancer model gene expression data are first harmonized (Module 1). Transparent machine learning by sparse discriminant analysis (SDA) is applied by combining predication accuracy and SDA-based deviance score for pre-selecting candidate cancer models (Module 2). Pathway-specific mechanistic explorations are iteratively investigated to conclude the final representative cancer model (Module 3). Blue frames represent input data, orange frames for essential output results, parallelogram frames for intermediate results, rectangular frames for analysis process, bullet-shaped frames for visualization, and rhombus frames for decision making.</p

Heatmap of pathway-specific deviance scores (<i>DS</i>_<i>path</i>) with 53 pathways (rows) and 9 genome-wide pre-selected cell lines +1 manually selected cell line (MDA-MB-134VI) (columns).

The genome-wide SDA projected deviance score (DSSDA) is shown on the top sidebar and the pathway size and normalized enrichment score (NES) are on the left. (TIF)</p

Cross-cancer validation of CASCAM.

(A) Genome-wide preselection identifies 5 out of 24 liver cell lines as ILC. (B) Pathway-based heatmap reveals that these 5 preselected cell lines significantly diverge from the ILC tumor center in terms of differentially expressed genes and associated pathways. (TIF)</p

Topological plots for APWG05PF7 (PDX.1B) and V1-organoid (PDO) from the same patient (171881–09-R) in KEGG Cell Adhesion Molecules.

(A) APWG05 (PDX.1B). (B) V1-organoid (PDO.1). (TIF)</p

Summary table of the pathway specific analysis for 9 unbiased-selected + 1 manually-included cell lines and 14 unbiased-selected +1 manually-included pathways.

Summary table of the pathway specific analysis for 9 unbiased-selected + 1 manually-included cell lines and 14 unbiased-selected +1 manually-included pathways.</p

Violin plot for CAMA1 and CDK4 in KEGG Cell Adhesion Molecules.

Violin plot for CAMA1 and CDK4 in KEGG Cell Adhesion Molecules.</p

UMAP of Celligner alignment between tumors and PDX/PDO models.

(A) Three distinct clusters were observed. The small cluster on the left consists of a seemingly rare breast cancer subtype, the upper-right cluster includes mostly non-basal samples, and the lower-right cluster includes mostly basal samples. (B) UMAP is redrawn when the small cluster in (A) is removed. (TIF)</p

Pathway- and gene-specific analysis for selection of representative cell line(s).

(A) Heatmap of pathway-specific deviance scores (DSpath) with 14 unbiased-selected and 1 manually-included pathways (30 size NES| > 1.5; shown on the rows) and 9 unbiased-selected and 1 manually-included cell lines (columns). The genome-wide SDA projected deviance score (DSSDA) is shown on the top side-bar and the pathway size and normalized enrichment score (NES) are on the left. Positive (negative) NES indicates up-regulation (down-regulation) in ILC compared to IDC. Average of the 14 pathways and the pre-selected “KEGG Cell Adhesion Molecules” pathway are shown at the bottom. The p-values of DSpath are annotated in the heatmap (one circle: p − value p − value p − value DSgene for the 10 selected cell lines and 22 DE genes in “KEGG Cell Adhesion Molecules” pathway. (C) Part of KEGG PathView topological networks for BCK4 (DSpath = 1.323) for the “KEGG Cell Adhesion Molecules” pathway. The result shows discordance of 10 genes in BCK4 (orange stars showing up-regulation compared to ILC tumors and blue start showing down-regulation).</p

Selecting representative PDO/PDX for ILC.

(A) SDA projected positions for PDO and PDX models from PDMR. Four models (three PDXs and one PDO; red circles) from the same patient (171881–019-R) were identified as candidate ILC models. Six models from this patient are labeled with the sample ID. High consistency was observed between SDA deviance scores and passages among PDX models. (B) Six models originated from the same patient were used for pathway-specific analysis. Six models show high congruence in the majority of 14 pathways and the Cell Adhesion pathway. (C) Violin plot shows the position of PDO.1 and PDX.1B on the six genes on which PDO.1 is discordant with.</p

Confusion matrix of genome-wide predication for HER2+, ER+/PR+, and TNBC prediction.

Confusion matrix of genome-wide predication for HER2+, ER+/PR+, and TNBC prediction.</p