Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Nat Genet. 2024 Nov;56(11):2466-2478. doi: 10.1038/s41588-024-01890-9. Epub 2024 Sep 3.
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.
结合细胞内在特性，肿瘤微环境中的相互作用调节治疗反应。我们利用单细胞空间转录组学来剖析人类胰腺癌中新辅助化疗和放疗相关的细胞间相互作用和细胞重塑。我们开发了受空间约束的最优传输交互分析（SCOTIA），这是一种最优传输模型，其代价函数既包括空间距离，也包括配体-受体基因表达。我们的结果揭示了治疗后癌相关成纤维细胞和恶性细胞之间配体-受体相互作用的显著变化，这一结果得到了包括体外肿瘤类器官共培养系统在内的正交数据集的支持。我们鉴定出富含白细胞介素-6 家族信号，该信号赋予了对化疗的抗性。总的来说，这项研究表明，使用单细胞空间转录组学对肿瘤微环境进行特征描述，可以识别可能在治疗抵抗出现中起作用的分子相互作用，并提供了一个可广泛应用于其他情况的基于空间的分析框架。
