Spatial Mapping of the Precancer-to-Cancer Transition in Breast and Prostate.
UNLABELLED: Breast and prostate cancers are both hormone-driven adenocarcinomas that undergo analogous invasion programs. Using lightsheet microscopy on intact tumors, we identified transitional junctions between precancerous and invasive regions. We then developed a multimodal serial-section workflow integrating volumetric reconstruction with spatial transcriptomics. Analysis of 319 spatial assays from 51 cases revealed gene expression features and novel structural insights defining the shift from precancer to invasive disease. In breast cancer, loss of MGP and PLAT was associated with invasive transition and promoted tumorigenesis in functional assays. In prostate cancer, GDF15, ALDH1A3, ANPEP, and FASN were upregulated along invasive progression, and their knockdown in PC-3 cells suppressed proliferation and migration. Enrichment of tumor-associated macrophages (SPP1+ and MS4A6A+) along non-triple-negative breast cancer breast cancer transitions highlights immune involvement as a potential driver of invasiveness. SIGNIFICANCE: Our method of defining precise spatial locations of invasive transition allows for the direct interrogation of transition drivers, presenting new therapeutic targets for the two most prevalent cancers and providing a framework for studying spatially defined mechanisms of tumor progression. See related commentary by Jing and Li, p. 1720.