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Nucleophosmin sustains WNT-driven cell proliferation and tumour initiation in vivo

ABSTRACT: Nucleophosmin (NPM1) is a nucleolar protein frequently mutated in haematopoietic malignancies and overexpressed in many solid tumours, but little is known about its functional role in carcinogenesis. Here, we identify NPM1 as a commonly upregulated gene following APC loss in tissues that positively respond to high WNT signalling. High NPM1 expression correlates with increased proliferation in patients with colorectal cancer (CRC). We show that whilst dispensable for adult epithelial tissue homeostasis, NPM1 loss has a profound effect on WNT-driven intestinal and liver tumourigenesis, leading to reduced proliferation and extension of survival. Mechanistically, NPM1 depletion triggers integrated stress response (ISR) and p53 pathway activation. Genetically or chemically blunting these pathways, rescues proliferation following NPM1 loss. Overall, our results demonstrate that NPM1 supports WNT-driven cell proliferation and tumour initiation by attenuating induction of ISR and p53 pathway activation. Being dispensable for homeostasis, NPM1 presents itself as a promising target for cancer therapy in WNT-driven tumours with functional p53, including treatment-refractory KRAS-mutant CRC and hepatic cancers.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Small Intestine

DISEASE(S): Colorectal Cancer

SUBMITTER: Sergio Lilla

LAB HEAD: Martin Bushell

PROVIDER: PXD062969 | Pride | 2025-08-12

REPOSITORIES: Pride

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			Action	DRS
	20231010_SEL_HF_SA_CHG_R11_160823_Npm1_TMT16_f001.raw	Raw
	20231010_SEL_HF_SA_CHG_R11_160823_Npm1_TMT16_f002.raw	Raw
	20231010_SEL_HF_SA_CHG_R11_160823_Npm1_TMT16_f003.raw	Raw
	20231010_SEL_HF_SA_CHG_R11_160823_Npm1_TMT16_f004.raw	Raw
	20231010_SEL_HF_SA_CHG_R11_160823_Npm1_TMT16_f005.raw	Raw

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Project description:The t(11;22)(p13;q12) translocation is pathognomonic for the highly aggressive desmoplastic small round cell tumour (DSRCT). The translocation fuses exon 7 of the EWS gene to exon 8 of the WT1 gene (EWS/WT1). Two splice variants of EWS/WT1 exist, arising from the presence (+KTS) or absence (-KTS) of three amino acids: lysine, threonine and serine between zinc fingers 3 and 4. To investigate the oncogenic properties of both isoforms of EWS/WT1, we over-expressed EWS/WT1 in untransformed murine embryonic fibroblasts (MEFs). We demonstrate that neither isoform of EWS/WT1 is sufficient to transform wild type MEFs, however the oncogenic potential of both isoforms is unmasked by the loss of p53. Expression of EWS/WT1 in MEFs lacking at least one allele of p53 resulted in enhanced cell proliferation, clonogenic survival and anchorage-independent growth. In addition EWS/WT1 expression in wild type MEFs attenuated several p53-dependent responses, including cell cycle arrest after irradiation and daunorubicin induced apoptosis. We show that DSRCT commonly have copy number amplification of MDM2 and MDMX, suggesting loss of p53 function in the tumours. Expression of either isoform of EWS/WT1 in MEFs induced characteristic mRNA expression profiles, including up-regulation of canonical Wnt pathway signaling. This was validated in cell lines and in a series of DSCRT, which confirmed canonical Wnt pathway activation in the tumours. We show for the first time that both isoforms of EWS/WT1 have oncogenic potential and that in addition to co-operating with loss of p53 function can also further attenuate p53-mediated responses. In addition we provide the first link between EWS/WT1 and Wnt pathway signaling. These data provide novel insights into the function of the EWS/WT1 fusion protein which characterizes DSCRT. Four independently generated pools of wild type MEFs were infected with tetracycline repressible EWS/WT1+KTS, EWS/WT1-KTS or GFP, selected with hygromycin and protein expression confirmed. Four GFP, four KTS+ and four KTS- samples were hybridized to the Ilumina BeadChip.

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Nucleophosmin sustains WNT-driven cell proliferation and tumour initiation in vivo

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