Integrated multi-omics reveals the cellular and molecular interactions governing the invasive niche in skin cancer

To progress, tumors need to invade the surrounding tissues. However, the heterogeneity of cell types at the tumor-stroma interface and the complexity of their potential interactions hampered mechanistic insights for efficient therapeutic targeting. Here, combining single-cell and spatial transcriptomics on human basal cell carcinomas (BCCs), we define the cellular contributors of the invasive front. In the invasive niche, tumor cells harbor a collective migration phenotype, supported by the expression of cell-cell junction complexes. In physical proximity, we identify cancer-associated fibroblasts (CAFs) with extracellular matrix-remodeling features, as required to support collective migration. Moreover, while tumor cells specifically express Activin A, we find Activin A-induced gene signature enrichment in adjacent CAFs subpopulations, further supporting their biological crosstalk. Altogether, our data identify the subpopulations and their transcriptional reprogramming contributing to the spatial organization of the BCC invasive niche. They also bring the proof-of-concept for integrated spatial and single-cell multi-omics to decipher cancer-specific invasive properties and develop therapeutic targeting. Overall design: Fresh basal cell carcinoma tumors of two patients were minced and enzymatically dissociated to single cell suspension. All single living cells were FACS-sorted and processed with the Chromium Next GEM single cell 3' reagent v3.1 kit (10x Genomics) to perform single cell RNA sequencing. Sequencing was performed on an Illumina HiSeq 4000 device. The sequence reads that passed quality filters were analyzed with Seurat R package (v.4.0.1).