Integrated spatial proteomics of human PDAC uncovers an expanded tumour–immune–stroma spectrum with genomic associations

Abstract 

Distinctively, pancreatic ductal adenocarcinoma (PDAC) consists of sparse tumour lesions intertwined with extensive desmoplastic stroma. The complexity of tumour–microenvironment interactions within the desmoplasia poses a challenge for accurate tumour profiling and patient stratification, and contributes to all tumours becoming profoundly resistant to therapy. Here we mapped the spatial relationships between tumour, stroma, and immune cell compartments delineating tumour and microenvironment types that expand the classical to basal spectrum of human PDAC. We used imaging mass cytometry to profile the in situ multi-cellular organization of 81 cell types in resected cases with paired whole genome sequencing. Cell types, functions, and pathway activation were distributed as highly reproducible environments in discrete locations throughout these tumours, which we deep-profiled using laser-capture mass spectrometry. We show that the connections between tumour phenotype, vascularization, immune response, and stromal biophysical state are reinforced by genomic aberrations, altered by treatment, and associated with patient outcome. Predictive machine-learning models showed that spatial single cell data outperformed genomic or clinical features but integrated multi-omics models provide the best prediction of patient survival with compressed models requiring only 10 non-redundant robust molecular measures associated with the phenotypic spectrum of PDAC. Together, these findings define a phenotypic and molecular framework of PDAC that captures tumour–microenvironment co-dependencies and offers a refined basis for patient stratification and therapeutic targeting.

Bio

Dr. Jackson completed his training in breast cancer in Toronto prior to a post-doctoral fellowship at the University of Zurich developing technology to study cell organization in human tissues and computational analysis for high dimension pathology. Dr. Jackson is now an investigator at the Lunenfeld Tanenbaum Research Institute and the Ontario Institute for Cancer Research, and is an Assistant Professor in the Department of Molecular Genetics at the University of Toronto. Dr. Jackson's research group is focused on understanding tissues and tumours as the integrated outcome of their single cell components. To do so, they develop and utilize experimental and computational methods for the measurement of spatially resolved single cells in structured tissues. This high-throughput, systematic approach allows us to simultaneously quantify tissue features at multiple scales, from rare single cells to multi-cellular tissue architectures. By studying these features in diverse model systems and large clinical cohorts they aim to identify and target the multi-cellular tumour microenvironments that drive disease progression and therapeutic resistance. They develop single cell pathology approaches to precision medicine and identified multi-parameter and topographical biomarkers of disease outcome in solid cancers. They strive to unravel the complex cellular environments driving cancer progression and maintaining tissue homeostasis, and are developing methods to quantify currently unmeasurable cell functions and screen for signaling factors controlling cellular ecosystems.