Journal Article

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

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

2022

Overview

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve 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. A multi-omic analysis of pancreatic cancer identifies spatially resolved, heterogeneous cell populations including transitional cell types. Analysis of primary samples identifies treatment-related changes in cross-talk between tumor and stromal cells.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/699/67/1504/1713 / 692/699/67/327 / Adenocarcinoma / Agriculture / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / Carcinoma, Pancreatic Ductal - metabolism / Cell cycle / Cell proliferation / Cell Transformation, Neoplastic - genetics / Cellular stress response / Copy number / Fibroblasts / Gene expression / Gene Function / Gene sequencing / Human Genetics / Humans / Immunoregulation / Inflammation / Lymphocytes / Lymphocytes T / Mesenchyme / Metallothioneins / Metaplasia / Microenvironments / Morphology / Mutation / Nectin / Pancreas - metabolism / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - metabolism / Pathology / Patients / Population / Populations / Proteomics / Quality control / Subpopulations / Transcriptomics / Tumor cells / Tumor Microenvironment - genetics / Tumors