美国哈佛医学院William L. Hwang等研究人员合作发现，胰腺癌的空间解析研究揭示与治疗相关的肿瘤微环境重塑。这一研究成果于2024年9月3日在线发表在国际学术期刊《自然—遗传学》上。

研究人员利用单细胞空间转录组学解析了与新辅助化疗和放疗相关的人类胰腺癌中多细胞邻域和细胞间相互作用的重塑过程。研究人员开发了空间约束最优传输相互作用分析（SCOTIA），这是一种最优传输模型，其成本函数包括空间距离和配体-受体基因表达。

研究人员发现，在治疗后，癌相关成纤维细胞与恶性细胞之间的配体-受体相互作用发生了显著变化，这一发现得到了包括体外类肿瘤共培养系统在内的多种数据集的支持。研究人员还发现白细胞介素-6家族信号通路的富集功能性赋予了对化疗的抗性。总体而言，该研究表明，利用单细胞空间转录组学对肿瘤微环境的表征，可以识别可能在治疗抗性产生中发挥作用的分子相互作用，并提供了一个可广泛应用于其他背景的空间分析框架。

据了解，肿瘤微环境中的相互作用与细胞内在特性共同调节治疗反应。

附：英文原文

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

Author: Shiau, Carina, Cao, Jingyi, Gong, Dennis, Gregory, Mark T., Caldwell, Nicholas J., Yin, Xunqin, Cho, Jae-Won, Wang, Peter L., Su, Jennifer, Wang, Steven, Reeves, Jason W., Kim, Tae Kyung, Kim, Youngmi, Guo, Jimmy A., Lester, Nicole A., Bae, Jung Woo, Zhao, Ryan, Schurman, Nathan, Barth, Jamie L., Ganci, Maria L., Weissleder, Ralph, Jacks, Tyler, Qadan, Motaz, Hong, Theodore S., Wo, Jennifer Y., Roberts, Hannah, Beechem, Joseph M., Castillo, Carlos Fernandez-del, Mino-Kenudson, Mari, Ting, David T., Hemberg, Martin, Hwang, William L.

Issue&Volume: 2024-09-03

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. Spatial molecular imaging analysis of human pancreatic adenocarcinomas describes multicellular neighborhoods in the tumor microenvironment. Ligand–receptor analysis using optimal transport-based SCOTIA identifies interleukin-6 as a mediator of chemoresistance.

DOI: 10.1038/s41588-024-01890-9

Source: https://www.nature.com/articles/s41588-024-01890-9