Abstract
The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.
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Data availability
All genomic datasets are available at the Gene Expression Omnibus database under accession code GSE229062. KLM1 H3K27ac, BxPC3 TP63 knockout and SUIT2 ΔNp63 overexpression ChIP–seq data in Extended Data Fig. 1b were obtained from previous studies18,21. The cancer dependency and expression datasets were obtained online at https://depmap.org/portal/download/ (DepMap Public 21Q4).
Code availability
No custom code was generated for this study. Details of all software packages used for data processing and analysis are provided in the appropriate section of Methods.
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Acknowledgements
We acknowledge B.W. Stillman, M.G. Hammell and J.M. Sheltzer for discussions and suggestions throughout the course of this study. This study was supported by the Cold Spring Harbor Laboratory NCI Cancer Center Support under grant CA045508. C.R.V. was supported by the Pershing Square Sohn Cancer Research Alliance, NCI grants CA013106-Project 1 and CA229699, and the Cold Spring Harbor Laboratory and Northwell Health Affiliation. D.M.-S. was supported by a Boehringer-Ingelheim Fonds Ph.D. fellowship. D.J.T. was supported by R35 GM139550 and A.C.S. was supported in part by T32 GM008759. D.L.S. was supported by NCI P01CA013106-Project 3. A.R.K. was supported by NCI P01CA013106-Project 2.
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Contributions
D.M.-S. and C.R.V. conceived this project, designed the experiments and wrote the paper with input from all of the authors. D.M.-S. performed the experiments and analyzed the data with the following help: A.C.S. isolated MKM and performed glycerol gradients in Fig. 3f; D.S. conducted cell culture and cell sorting for basal lineage CRISPR screens; P.J.C. performed scRNA-seq and non-PDAC RNA-seq and western blot experiments; M.C.T. analyzed scRNA-seq data and C.O.d.S. provided advice; P.M. and X.Y.H. performed orthotopic transplantation experiments and D.T.F. and M.E. provided advice; Y.G. performed flow cytometry cell cycle and MKM knockout pulldown experiments; V.K. performed knockdown RNA-seq and cell proliferation competition experiments; D.L.S. provided advice on basal breast organoids; Y.S. performed culturing and experiments on breast organoids; L.W. performed non-PDAC western blot experiments and A.R.K. provided advice; A.A. and J.L. helped establish systems for Mediator complex expression in Sf9; C.R.V. and D.J.T. supervised the studies. C.R.V. acquired the funding.
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Competing interests
C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer-Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. D.J.T. is a member of the SAB at Dewpoint Therapeutics. D.L.S. is a member of the Scientific Advisory Board of Flamingo Therapeutics and Amaroq Therapeutics. A.R.K. is a Founder, Director and Chair of the SAB of, and owns stock in, Stoke Therapeutics; serves on the SABs of Skyhawk Therapeutics, Envisagenics and Autoimmunity BioSolutions; and is a consultant for Biogen and Seed Therapeutics. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 KRT5 expression is directly regulated by ΔNp63 and MED12 controls basal marker gene expression.
a, Western blot of CRISPRi-mediated TP63 knockdown in KLM1 cells. b, ChIP–seq genomic occupancy tracks18 zoomed in the KRT5 locus. The two upper tracks show normalized enrichment of endogenous (BxPC3) or overexpressed (ΔNp63-FLAG SUIT2) ΔNp63. The bottom four tracks show H3K27ac normalized enrichment after GFP or ΔNp63 overexpression in SUIT2 cells or ROSA26 or TP63 knockout in BxPC3 cells. ChIP signal was calculated using deepTools with the option BamCompare subtract to normalize each sample to its input. All tracks plotting ChIP data obtained with the same antibody are plotted in the same scale. c–e, Western blot of basal-like markers in TP63 or MED12 knockout human patient-derived basal-like PDAC organoid hF3 (c), HNSCC (Cal33), SSCC (Hsc5), basal-like TNBC (HCC1806) and ESCC (KYSE70 and KYSE410) human cancer cell lines (d), and patient-derived TNBC organoid NH93T (e). HNSCC: head and neck squamous cell carcinoma; SSCC: skin squamous cell carcinoma; TNBC: triple-negative breast cancer; ESCC: esophageal squamous cell carcinoma.
Extended Data Fig. 2 MED12 and ΔNp63 co-regulate the basal gene expression program.
a, Representative GSEA plots of KLM1 MED12 knockout using gene signatures derived from human basal PDAC tumors10 and direct ΔNp63 gene targets in PDAC18. Three biological replicates were used for each sample. Complete GSEA analysis for all the sgRNA and cell lines tested can be found in Supplementary Table 3. b, Representative GSEA plots of HCC1806 (basal-like TNBC) and Cal33 (HNSCC) MED12 knockout using ΔNp63 target gene signatures. Two biological replicates were used for each sample, and two different sgRNAs were tested per gene. Complete GSEA analysis for all the sgRNA tested can be found in Supplementary Table 4. c, UMAPs of BxPC3 (top row), T3M4 (middle row) and hF3 (bottom row) scRNA-seq upon CRISPR knockout of TP63 or MED12. Each unique cell sequenced is colored according to its knockout genotype on the leftmost column to illustrate the distribution of cells in the UMAP. UMAP heatmaps colored by intensity of basal-like PDAC18, classical PDAC10 and Interferon alpha/beta (MSigDB R-HSA-909733 v2023.1) signatures are shown on the right. Pre-processing and data filtering were performed as described in Methods. d, Violin plots of gene expression of basal-like marker genes KRT5 and KRT6A, classical genes GATA6 and CEACAM6 and Interferon-related genes IFI6 and IFI27 across BxPC3, T3M4 and hF3 knockout scRNA-seq. When density of cells expressing non-negligible levels of assessed genes was low across all conditions, individual cell expression values were depicted as single dots. e, Time-course RT-qPCR of S100A2 after lentiviral infection with CRISPRi sgRNA targeting TP63 (2 sgRNA), MED12 (3 sgRNA), non-targeting sgRNAs (2 sgRNA) or uninfected control T3M4 cells. −ΔΔCt values are plotted as the average of each sgRNA normalized to the average of housekeeping genes ACTB and B2M (three measurements per condition). For each gene perturbation, the average −ΔΔCt value is shown in a solid line, and the 95% confidence intervals are shown as translucid intervals. The inflection points of TP63 and other basal markers upon MED12 knockdown (~day 5) is marked by a vertical black dashed line.
Extended Data Fig. 3 MED12 and ΔNp63 co-occupy basal-like loci.
a, Metaplot of genomic occupancy of ΔNp63 and MED12 centered around ΔNp63 peaks in T3M4 cells. b, ChIP–seq tracks of ΔNp63, MED12 and H3K27ac normalized occupancy at select basal-specific ΔNp63 direct target loci in KLM1 cells upon ROSA26 or TP63 knockout (sgRNA, 2). Normalized enrichment values were generated with deepTools bamCoverage -RPCG. c, Western blot of SUIT2 CRISPR-activated TP63 (ΔNp63 isoform-specific) cells. BxPC3, which endogenously expresses the ΔN isoform of p63, is shown as a positive control in the rightmost lane. d, Genomic tracks of ΔNp63 and MED12 occupancy at direct ΔNp63 targets ANXA8, S100A2 and ANXA8L1 in SUIT2-VPR lines infected with non-targeting (NT) or TP63-targeting sgRNAs. a,b,d, One independent measurement is shown per condition.
Extended Data Fig. 4 Characterization of recombinantly expressed and purified full length MBP-p63 protein and MKM-dependent association of ΔNp63 with Mediator.
a, Silver stain of full length purified MBP-ΔNp63. The single protein band was confirmed to be the expected MBP-ΔNp63 peptide by western blotting and mass spectrometry. b, Silver stain of 0.025% glutaraldehyde crosslinked (‘xlinked’) and input purified full length MBP-ΔNp63, MBP-ΔNp63 truncation mutant (DO, DBD through OD), MBP-EGFP or MBP alone. c, Western blot of DNA pulldown experiment using purified proteins and biotinylated DNA oligos containing the p63-binding sequence of the CDKN1A promoter or a scramble DNA control. d, Competition-based proliferation assays in Cas9-expressing T3M4 (top row) and BxPC3 (bottom row) cells after lentiviral expression of the indicated sgRNA pairs linked with GFP. Bars represent the mean normalized percentage of GFP to day 3 after infection, and dots represent independent measurements (n=3 biological replicates). e, Transcripts per million gene expression levels of paralog pairs of the MKM in T3M4 and BxPC3 cell lines. Data extracted from the CCLE dataset. f, Principal component analysis of gene expression changes upon MKM paralog double knockout. MED12, MED12/MED12L and MED13/MED13L double knockouts are encircled together. g, Scatterplots depicting gene expression changes in MED12 or MED12/MED12L knockout T3M4 cells. DESeq2-derived log2(FC) of all significantly expressed genes in three biological replicates per sgRNA are plotted. Select basal genes are highlighted in yellow. h, Western blot of MBP or MBP-ΔNp63 pulldown of endogenous Mediator components from nuclear lysates of ROSA26, CCNC or CDK8/CDK19 knockout HEK293T cells.
Extended Data Fig. 5 MED12 is a preferential genetic dependency in basal-like PDAC.
a, Western blots of T3M4 cells stably expressing N-FLAG-tagged overexpressed truncated ΔNp63 cDNA used in gene complementation assays in Fig. 4b. b, Coomassie blue of purified MBP-ΔNp63 mutants lacking the DNA-binding domain (ΔDBD) or oligomerization domain (ΔOD). c, Crystal violet staining of basal-like (T3M4, BxPC3) or classical (CFPAC1, Panc-1) knockout cell lines of TP63, MED12, or pan-essential core Mediator subunits MED11 and MED14. d, Luminescence reading of CellTiter-Glo assay at day 8 post-infection with lentivirally-encoded sgRNA (n=2–3 independent replicates). Two-sided t-test p-values are shown in the figure. e, Orthotopically transplanted basal-like ΔNp63+ (T3M4) or ΔNp63- (Panc-1) knockout cells were followed over time by luciferase imaging (n=4 mice per group per cell line). Growth of TP63 and MED12 knockout tumor cells was compared with that of negative control (ROSA26 targeting sgRNA) and core Mediator (pan-essential MED30) knockout. Average of independent sample measurements is shown per timepoint, with error bars depicting the standard error of the mean. f, Resected tumor weight at endpoint in T3M4 and Panc-1 knockout cells (n=4 mice per group per cell line). Independent tumor samples are shown as dots, and their average value is shown as bars along with error bars depicting the standard error of the mean. The fold decrease in tumor mass compared to ROSA26 knockout is shown next to the bar of each additional knockout condition. A one-way ANOVA was conducted to detect any overall differences among the groups, followed by Dunnett’s test to compare each sgRNA knockout against the ROSA26 knockout control. P-values are displayed to indicate the significance of these comparisons. g, Images of resected of T3M4 and Panc-1 orthotopic tumors. An asterisk indicates that despite initial injection of tumor cells, no tumor mass could be found at endpoint.
Extended Data Fig. 6 Flow cytometry-based cell cycle profiling reveals growth arrest in TP63 and MED12 knockout cells.
a, Flow cytometry plots of BxPC3 (top) or T3M4 (bottom) knockout cells stained with propidium iodide (y-axis) and AF647-Annexin V (x-axis). Events shown were previously gated on singlets by FSC-H vs FSC-W. Percentages of events relative to the total number of gated events is shown in each quadrant. b, Stacked bar plot representing the distribution of singlets in each cell cycle phase by BrdU staining in BxPC3 (left) or T3M4 (right) knockout cells. Each stacked bar represents the distribution of events for an independent measurement. Two-sided t-test p-value of proportion of cells in S phase are shown in the figure. c, Competition-based proliferation assays in Cas9-expressing Cal33 (HNSCC), Hsc5 (SSCC), HCC1806 (TNBC), KYSE70 (ESCC) and KYSE410 (ESCC) after lentiviral expression of TP63- or MED12-targeting sgRNAs. Bars represent the mean percentage GFP normalized to day 3 post-infection, and dots represent independent measurements (n=2 biological replicates). HNSCC: head and neck squamous cell carcinoma; SSCC: skin squamous cell carcinoma; TNBC: triple-negative breast cancer; ESCC: esophageal squamous cell carcinoma.
Supplementary information
Supplementary Information
Supplementary Methods.
Supplementary Tables
Supplementary Table 1: Marker-based CRISPR screening results. Supplementary Table 2: PDAC cell lines classification by basal-like and classical gene signatures. Supplementary Table 3: GSEA results and gene signatures of TP63/MED12 knockout RNA-seq in basal-like PDAC cell lines. Supplementary Table 4: GSEA results and gene signatures of TP63/MED12 knockout RNA-seq in non-PDAC basal/squamous cell lines. Supplementary Table 5: Basal lineage loci from ChIP–seq experiments. Supplementary Table 6: GSEA results and gene signatures of MKM paralog knockout RNA-seq. Supplementary Table 7: GSEA results and gene signatures of CDK8/CDK19 inhibitor treatment RNA-seq. Supplementary Table 8: Mediator complex exon scan library and CRISPR screen results. Supplementary Table 9: sgRNA and RT-qPCR primer sequences. Supplementary Table 10: Genetic demultiplexing of single-cell RNA-seq. Supplementary Table 11: Antibodies and reagents.
Source data Figs. 1, 3 and 4 and Extended Data Figs. 1 and 3–5
Unprocessed western blots and crystal violet stains.
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Maia-Silva, D., Cunniff, P.J., Schier, A.C. et al. Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma. Nat Genet 56, 1377–1385 (2024). https://doi.org/10.1038/s41588-024-01790-y
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DOI: https://doi.org/10.1038/s41588-024-01790-y
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