ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer

Nouruzi, Shaghayegh; Namekawa, Takeshi; Tabrizian, Nakisa; Kobelev, Maxim; Sivak, Olena; Scurll, Joshua M; Cui, Cassandra Jingjing; Ganguli, Dwaipayan; Zoubeidi, Amina

doi:10.1172/jci.insight.185952

JCI Insight

2024

DOI: 10.1172/jci.insight.185952

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ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer

Shaghayegh Nouruzi,

Takeshi Namekawa,

Nakisa Tabrizian

et al.

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2024

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Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer

Ireland,

Hawgood,

Xie

et al. 2024

Preprint

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Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes. The mechanisms driving neuroendocrine-tuft tumour heterogeneity, and the origins of tuft-like cancers are unknown. Using multiple genetically-engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovers unexpected transcriptional states and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss, and ASCL1 suppression, cooperate to promote tuft-like tumours. Transcriptomics of 944 human SCLCs reveal a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate remarkable conservation between cancer states and normal basal cell injury response mechanisms. Together, these data suggest that the basal cell is a plausible origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity-offering new insights for targeting lineage plasticity.

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Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer

Ireland,

Hawgood,

Xie

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer

Cited by 1 publication

References 68 publications

Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer

Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer

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