Journal
NATURE
Volume 607, Issue 7917, Pages 169-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04842-7
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Funding
- Cold Spring Harbor Laboratory NCI Cancer Center Support grant [CA045508]
- Pershing Square Sohn Cancer Research Alliance, National Institutes of Health [CA013106, CA242919]
- Department of Defense [W81XWH1910317]
- Cold Spring Harbor Laboratory
- William C. and Joyce C. O'Neil Charitable Trust
- Pershing Square Foundation
- 2021 AACR-AstraZeneca Breast Cancer Research Fellowship [21-40-12-HE]
- NIH [CA231997]
- Singapore National Science Scholarship (PhD) A*STAR
- Northwell Health
- U.S. Department of Defense (DOD) [W81XWH1910317] Funding Source: U.S. Department of Defense (DOD)
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Tuft cells are rare chemosensory cells that play a role in coordinating immune and neural responses to foreign pathogens. Recent studies have shown their involvement in small-cell lung cancer. This study reveals the critical role of POU2F3-OCA-T complex in tuft cell identity and its potential as a molecular vulnerability in small-cell lung cancer.
Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues(1). Recent studies have also revealed tuft-cell-like human tumours(2,3), particularly as a variant of small-cell lung cancer. Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F3 (refs.(2,4)), although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1/POU2AF2 and OCA-T2/POU2AF3, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogues of the B-cell-specific coactivator OCA-B; all three proteins are encoded in a gene cluster and contain a conserved peptide that binds to class II POU transcription factors and a DNA octamer motif in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft-cell-like small-cell lung cancer. Moreover, we generated OCA-T1-deficient mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal that the POU2F3-OCA-T complex is the master regulator of tuft cell identity and a molecular vulnerability of tuft-cell-like small-cell lung cancer.
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