LY6D marks pre-existing resistant basosquamous tumor subpopulations

Daniel Haensel, Sadhana Gaddam, Nancy Y. Li, Fernanda Gonzalez, Tiffany Patel, Jeffrey M. Cloutier, Kavita Y. Sarin, Jean Y. Tang, Kerri E. Rieger, Sumaira Z. Aasi and Anthony E. Oro ()
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Daniel Haensel: Stanford University School of Medicine
Sadhana Gaddam: Stanford University School of Medicine
Nancy Y. Li: Stanford University School of Medicine
Fernanda Gonzalez: Stanford University School of Medicine
Tiffany Patel: Stanford University School of Medicine
Jeffrey M. Cloutier: Stanford University School of Medicine
Kavita Y. Sarin: Stanford University School of Medicine
Jean Y. Tang: Stanford University School of Medicine
Kerri E. Rieger: Stanford University School of Medicine
Sumaira Z. Aasi: Stanford University School of Medicine
Anthony E. Oro: Stanford University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensive understanding of the cellular states and markers associated with these populations remains poorly understood. Here we identify a pre-existing resistant cellular population in naive basal cell carcinoma tumors marked by the surface marker LY6D. LY6D+ tumor cells are spatially localized and possess basal cell carcinoma and squamous cell carcinoma-like features. Using computational tools, organoids, and spatial tools, we show that LY6D+ basosquamous cells represent a persister population lying on a central node along the skin lineage-associated spectrum of epithelial states with local environmental and applied therapies determining the kinetics of accumulation. Surprisingly, LY6D+ basosquamous populations exist in many epithelial tumors, such as pancreatic adenocarcinomas, which have poor outcomes. Overall, our results identify the resistant LY6D+ basosquamous population as an important clinical target and suggest strategies for future therapeutic approaches to target them.

Date: 2022
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DOI: 10.1038/s41467-022-35020-y

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