Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment

Menée à partir de l'analyse transcriptomique spatiale d'échantillons tumoraux prélevés sur des patients atteints d'un cancer du pancréas et menée à l'aide de cocultures tridimensionnelles de fibroblastes CAFs et de cellules cancéreuses d'origine murine, cette étude met en évidence un remodelage du microenvironnement tumoral lié à un traitement néoadjuvant comportant une chimiothérapie de type FOLFIRINOX suivie d'une radiothérapie fractionnée en combinaison avec le 5-fluorouracile ou la capécitabine

Résumé en anglais

In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell–cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand–receptor gene expression. Our results uncovered a marked change in ligand–receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.