Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response.

We performed the first integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, cellular compositions, and ligand-receptor interactions. We demonstrate that LE regions are conserved across multiple cancers while TC states are more tissue specific, highlighting the existence of common mechanisms underlying tumor progression and invasion. Additionally, we found our LE gene signature is associated with worse clinical outcomes while the TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an <em>in silico</em> modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and a platform for data exploration (http://www.pboselab.ca/spatial_OSCC/) that can be foundational for developing novel targeted therapies. <br> Data uploaded: 1) .loom files as outputs of the scvelo pipeline for each object independently. 2) .Robj files for each of the 12 samples formatted as a Seurat object 3. ScPred model as a .Robj file