美国华盛顿大学Li Ding、Ryan C. Fields和David G. DeNardo研究团队合作发现，空间受限驱动因子和过渡细胞群在未经治疗和化疗耐药胰腺癌细胞微环境中相合作。相关论文于2022年8月22日发表在《自然-遗传学》杂志上。

研究人员利用单细胞/细胞核RNA测序、宏蛋白质组学、空间转录组学和细胞成像研究了来自31名患者（11名未接受治疗和20名接受治疗）的83个空间样本。肿瘤细胞亚群表现出增殖、KRAS 信号传导、细胞应激和上皮-间质转化的特征。映射突变和拷贝数改变将肿瘤群与正常和迁移细胞区分开来，包括腺泡-导管化生和胰腺上皮内瘤变。空间转录组数据的病理学辅助反卷积确定了具有不同组织学特征的肿瘤和过渡亚群。

研究展示了TIGIT在耗竭和调节性T细胞和肿瘤细胞Nectin的协调表达。化学抗性样品含有三倍富集的炎性癌症相关成纤维细胞，这些成纤维细胞上调金属硫蛋白。该研究揭示了对胰腺导管腺癌肿瘤复杂亚结构的更深入了解，这可能有助于改善对该疾病患者的治疗。

据介绍，胰腺导管腺癌是一种致命的疾病，治疗方式有限且患者的生存率低。

附：英文原文

Title: Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Author: Cui Zhou, Daniel, Jayasinghe, Reyka G., Chen, Siqi, Herndon, John M., Iglesia, Michael D., Navale, Pooja, Wendl, Michael C., Caravan, Wagma, Sato, Kazuhito, Storrs, Erik, Mo, Chia-Kuei, Liu, Jingxian, Southard-Smith, Austin N., Wu, Yige, Naser Al Deen, Nataly, Baer, John M., Fulton, Robert S., Wyczalkowski, Matthew A., Liu, Ruiyang, Fronick, Catrina C., Fulton, Lucinda A., Shinkle, Andrew, Thammavong, Lisa, Zhu, Houxiang, Sun, Hua, Wang, Liang-Bo, Li, Yize, Zuo, Chong, McMichael, Joshua F., Davies, Sherri R., Appelbaum, Elizabeth L., Robbins, Keenan J., Chasnoff, Sara E., Yang, Xiaolu, Reeb, Ashley N., Oh, Clara, Serasanambati, Mamatha, Lal, Preet, Varghese, Rajees, Mashl, Jay R., Ponce, Jennifer, Terekhanova, Nadezhda V., Yao, Lijun, Wang, Fang, Chen, Lijun, Schnaubelt, Michael, Lu, Rita Jui-Hsien, Schwarz, Julie K., Puram, Sidharth V., Kim, Albert H., Song, Sheng-Kwei, Shoghi, Kooresh I., Lau, Ken S., Ju, Tao, Chen, Ken

Issue&Volume: 2022-08-22

Abstract: Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-nave and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

DOI: 10.1038/s41588-022-01157-1

Source: https://www.nature.com/articles/s41588-022-01157-1