The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms

Chao-Hui Chang, Feng Liu, Stefania Militi, Svenja Hester, Reshma Nibhani, Siwei Deng, James Dunford, Aniko Rendek, Zahir Soonawalla, Roman Fischer, Udo Oppermann and Siim Pauklin ()
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Chao-Hui Chang: University of Oxford
Feng Liu: University of Oxford
Stefania Militi: University of Oxford
Svenja Hester: University of Oxford
Reshma Nibhani: University of Oxford
Siwei Deng: University of Oxford
James Dunford: University of Oxford
Aniko Rendek: Oxford University Hospitals NHS Foundation Trust
Zahir Soonawalla: Oxford University Hospitals NHS
Roman Fischer: University of Oxford
Udo Oppermann: University of Oxford
Siim Pauklin: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-29

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47680-z

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