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

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.

A Spatiotemporal and Machine-Learning Platform Accelerates the Manufacturing of hPSC-derived Esophageal Mucosa.

Human pluripotent stem cell-derived tissue engineering offers great promise in designer cell-based personalized therapeutics. To harness such potential, a broader approach requires a deeper understanding of tissue-level interactions. We previously developed a manufacturing system for the ectoderm-derived skin epithelium for cell replacement therapy. However, it remains challenging to manufacture the endoderm-derived esophageal epithelium, despite both possessing similar stratified structure. Here we employ single cell and spatial technologies to generate a spatiotemporal multi-omics cell atlas for human esophageal development. We illuminate the cellular diversity, dynamics and signal communications for the developing esophageal epithelium and stroma. Using the machine-learning based Manatee, we prioritize the combinations of candidate human developmental signals for in vitro derivation of esophageal basal cells. Functional validation of the Manatee predictions leads to a clinically-compatible system for manufacturing human esophageal mucosa. Our approach creates a versatile platform to accelerate human tissue manufacturing for future cell replacement therapies to treat human genetic defects and wounds.

Skin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche.

Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the heterogeneous basal cell carcinoma tumor epithelia. Within the highly proliferative neighborhood, we find that TREM2+ skin cancer-associated macrophages (SCAMs) support the proliferation of a distinct tumor epithelial population through an immunosuppression-independent manner via oncostatin-M/JAK-STAT3 signaling. SCAMs represent a unique tumor-specific TREM2+ population defined by VCAM1 surface expression that is not found in normal homeostatic skin or during wound healing. Furthermore, SCAMs actively proliferate and self-propagate through multiple serial tumor passages, indicating long-term potential. The tumor rapidly drives SCAM differentiation, with intratumoral injections sufficient to instruct naive bone marrow-derived monocytes to polarize within days. This work provides mechanistic insights into direct tumor-immune niche dynamics independent of immunosuppression, providing the basis for potential combination tumor therapies.