Basal-to-inflammatory transition and tumor resistance via crosstalk with a pro-inflammatory stromal niche

Nancy Yanzhe Li, Weiruo Zhang, Daniel Haensel, Anna R. Jussila, Cory Pan, Sadhana Gaddam, Sylvia K. Plevritis and Anthony E. Oro ()
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Nancy Yanzhe Li: Stanford University School of Medicine
Weiruo Zhang: Stanford University School of Medicine
Daniel Haensel: Stanford University School of Medicine
Anna R. Jussila: Stanford University School of Medicine
Cory Pan: Stanford University School of Medicine
Sadhana Gaddam: Stanford University School of Medicine
Sylvia K. Plevritis: Stanford University School of Medicine
Anthony E. Oro: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialized inflammatory microenvironment.

Date: 2024
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DOI: 10.1038/s41467-024-52394-3

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