Basal-to-Inflammatory Transition Contributes to Basal Cell Carcinoma Therapy Resistance via Crosstalk with a Pro-Inflammatory Stromal Niche

Overcoming tumor evolution and inducible resistance states remain the main challenge to creating successful anti-tumor therapies. The body's cancer-associated inflammatory response is a double-edged sword having ill-defined pro- and anti-tumor properties. Our group previously identified a basal cell carcinoma (BCC) tumor-intrinsic resistance pathway called basal to squamous cell carcinoma transition (BST). However, tumor resistance driven through the complex dynamics of tumor interactions with the inflammatory response remains poorly studied. Here, employing a multipronged approach combining human tumor single-cell transcriptomics, single-cell chromatin accessibility (scATAC-Seq) study, CODEX multiplexed imaging, spatial transcriptomic along with functional validation, we have identified a surprising inflammation-associated SMOi therapy enriched tumor epithelial cell state we term basal-to-inflammatory transition (BIT). Marked by CHI3L1, TAGLN, ITGAV, and VCAM1, BIT arises in spatially distinct neighborhoods from BST in a subset of naive BCCs. While BST tumor epithelium occurs within the central cores of tumor nodules, BIT tumor epithelium arises in a specialized inflammatory environment defined by a tumor associated TREM1 myeloid signature. IL1 and OSM secreted by TREM1 myeloid cells activate the inflammatory NF-kB family of transcription factors within the BIT tumor epithelium. Strikingly, IL1 and OSM ligands are sufficient not only in inducing the BIT tumor state in vitro and in vivo in a synergistic fashion but also in lowering the sensitivity of human BCC explant tumors to SMOi treatment. This work provides critical insights into the BIT-resistant state as a novel targetable tumor state driven by a specialized inflammatory microenvironment.

• Study Design:
  • Case Set
• Study Type:
  • Case Set
  • RNA Sequencing
• Total number of consented subjects: 6
• Subject Sample Telemetry Report (SSTR)

• BioProject
• Sequence Read Archive
• BioSample
• MeSH
• Gene

Tissue samples were collected from Basal Cell Carcinoma patients.

• Primary Phenotype: Carcinoma, Basal Cell
• Single-Cell Gene Expression Analysis
• Tumor Microenvironment

• CHI3L1
• IL1A
• ITGAV
• OSM
• TAGLN
• TREM1
• VCAM1

• Principal Investigator
  • Anthony Oro. Department of Dermatology, Stanford University, Palo Alto, CA, USA.