Stem-cell states converge in multistage cutaneous squamous cell carcinoma development

• 成果类型: Article
• 署名作者: Taylor, Mark A.; Kandyba, Eve; Halliwill, Kyle; Delrosario, Reyno; Khoroshkin, Matvei; Goodarzi, Hani; Quigley, David; Li, Yun Rose; Wu, Di; Bollam, Saumya R.; Mirzoeva, Olga K.; Akhurst, Rosemary J.; Balmain, Allan
• 署名单位: University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Medical University of Bialystok; AbbVie; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; City of Hope; City of Hope; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8153
• DOI: 10.1126/science.adi7453
• 发表日期: 2024-05-31
• 关键词: hair follicle; regulatory networks; tumor initiation; self-renewal; cancer; lgr6; inflammation; architecture; plasticity; landscape

摘要

Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.