In situ multi-modal characterization of pancreatic cancer reveals tumor cell identity as a defining factor of the surrounding microenvironment [Spatial Transcriptomics]

Pancreatic Ductal Adenocarcinoma (PDAC) is heterogeneous with low tumor purity, prominent microenvironment and complex architecture, which preclude identification of shared tumor intrinsic biology within and across patients. We overcame these challenges by applying spatial omics approaches – providing necessary resolution and context – to primary untreated PDAC tumors from 39 patients capturing 340K low-bulk and 530K single-cell spatial transcriptomes. We observe a spectrum of classical-to-basal tumor subtypes present within all patients. We identify a distinct population of proliferative tumor cells enriched for the DNA synthesis-condensation-mitosis transcriptional network suggesting this subset disproportionately contribute to tumor growth. Furthermore, we characterize the microenvironment surrounding each tumor subtype and observe that basal identity is contextually defined by collagen, hypoxic adaptation and fibroblast neighbors expressing activated stroma and interferon stimulated gene therapy resistance signatures. Lastly, leveraging orthogonal patient, cell and mouse data, we determine which aspects of PDAC biology are recapitulated in bulk datasets and reductionist models.