Extended Data Fig. 4. Inhibition of the mitochondrial pyruvate carrier antagonizes luminal lineage identity.

(a) Intracellular flow cytometry of KRT8 and KRT5 in basal-derived organoids treated with 0-40 μM UK5099 for seven days. (b) Percent organoid formation of basal-derived organoids treated with 0-40 μM UK5099 (n = 3 independent biological replicates). (c) Percent organoid formation of vehicle- and 10 μM UK5099-treated luminal-derived organoids (n = 3 independent biological replicates). (d) Western blot analysis of proliferation markers (Ki67 and PCNA) and apoptosis marker (CC3, cleaved caspase-3) in vehicle- and 10 μM UK5099-treated luminal-derived organoids seven days after plating. (e) Correlation analysis of [U-¹³C]glucose fractional contribution comparing Mpc1-KO and 10 μM UK5099-treated basal-derived organoids (n = 3 independent biological replicates). (f) GSEA showing negative enrichment of CD49f^low luminal signature¹⁸ in 10 μM UK5099-treated relative to vehicle-treated basal-derived organoids. (g) GSEA showing enrichment of CD49f^high basal signature¹⁸ in vehicle-treated relative to 10 μM UK5099-treated basal-derived organoids. (h) GSEA showing enrichment of CD49f^high basal signature¹⁸ in control relative to Mpc1-KO basal-derived organoids. For all panels, error bars represent SEM. p-values were calculated using an unpaired two-tailed t-test with Welch’s correction. Correlation analysis was performed using Spearman’s correlation.

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