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The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.

Original publication




Journal article


Nat Commun

Publication Date





Humans, Neoplastic Stem Cells, Paracrine Communication, E2F1 Transcription Factor, Cell Line, Tumor, Pancreatic Neoplasms, E2F4 Transcription Factor, Animals, Carcinoma, Pancreatic Ductal, Wnt Proteins, Retinoblastoma Protein, Breast Neoplasms, p300-CBP Transcription Factors, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Female, Cell Proliferation, Mice, Signal Transduction, Drug Resistance, Neoplasm