2. Academic Validation
  3. Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer

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

  • bioRxiv. 2024 Nov 15:2024.11.13.623500. doi: 10.1101/2024.11.13.623500.
Abbie S Ireland 1,  Sarah B Hawgood 1,  Daniel A Xie 1,  Margaret W Barbier 1,  Scarlett Lucas-Randolph 1,  Darren R Tyson 1,  Lisa Y Zuo 1,  Benjamin L Witt 2,  Ramaswamy Govindan 3,  Afshin Dowlati 4,  Justin C Moser 5,  Sonam Puri 6,  Charles M Rudin 7,  Joseph M Chan 8,  Andrew Elliott 9,  Trudy G Oliver 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA.
  • 2 Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA.
  • 3 Division of Oncology, Department of Medicine, Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, 63110, USA.
  • 4 Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 5 HonorHealth Research Institute, Scottsdale, AZ, 85254, USA.
  • 6 Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • 7 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 8 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 9 Caris Life Sciences, Tempe, AZ, 85040, USA.
PMID: 39605338 DOI: 10.1101/2024.11.13.623500
Abstract

Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively1,2. Neuroendocrine cancers, including small cell lung Cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes3-13. 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 mechanisms14-18. 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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