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Updated: Jun 9, 2026
Isolation of Proximal Fluids to Investigate the Tumor Microenvironment of Pancreatic Adenocarcinoma
Published on: November 5, 2020
Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor
Carina Shiau1,2,3,4, Jingyi Cao5, Dennis Gong1,2,3,4,6
1Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
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.
Insights
Single-cell spatial transcriptomics revealed how tumor microenvironment interactions change during pancreatic cancer treatment. This identified interleukin-6 signaling as a key driver of chemotherapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Tumor microenvironment (TME) interactions significantly influence cancer treatment outcomes.
- Understanding these complex cellular crosstalks is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer under neoadjuvant therapy.
- To identify molecular mechanisms driving therapeutic resistance within the TME.
Main Methods:
- Utilized single-cell spatial transcriptomics to analyze TME composition and interactions.
- Developed spatially constrained optimal transport interaction analysis (SCOTIA) integrating spatial and gene expression data.
- Validated findings using orthogonal datasets, including ex vivo tumoroid coculture.
Main Results:
- Observed significant alterations in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells post-treatment.
- Identified enrichment of interleukin-6 (IL-6) family signaling pathways.
- Demonstrated that IL-6 signaling confers functional resistance to chemotherapy.
Conclusions:
- Single-cell spatial transcriptomics is a powerful tool for dissecting TME dynamics and identifying resistance mechanisms.
- The developed SCOTIA framework provides a novel approach for analyzing spatially resolved molecular interactions.
- Targeting IL-6 signaling may represent a therapeutic strategy to overcome chemotherapy resistance in pancreatic cancer.
