Combining spatial transcriptomics and ECM imaging in 3D for mapping cellular interactions in the tumor microenvironment
Tumors are complex ecosystems composed of malignant and non-malignant cells embedded in a dynamic extracellular matrix (ECM). In the tumor microenvironment, molecular phenotypes are controlled by cell-cell and ECMinteractions in 3D cellular neighborhoods (CNs). While their inhibition can impede tumor progres sion, routine moleculartumorprofilingfailstocapturecellularinteractions.Single-cell spatial transcriptomics (ST) mapsreceptor-ligand interactions butusually remainslimited to 2D tissue sections and lacks ECM read outs. Here, we integrate 3D ST with ECM imaging in serial sections from one clinical lung carcinoma to sys tematically quantify molecular states, cell-cell interactions, and ECM remodeling in CN. Our integrative anal ysis pinpointed known immuneescapeandtumorinvasionmechanisms,revealingseveral druggabledrivers of tumor progression in the patient under study. This proof-of-principle study highlights the potential of in depth CN profiling in routine clinical samples to inform microenvironment-directed therapies. A record of this paper’s transparent peer review process is included in the supplemental information
