Paper

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

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

2021

Overview

KRAS, SMAD4, and GNAQ, were associated with differential phosphosignaling and metabolic responses compared to wild type. Single cell subtyping discovered 12 of 21 tumors with mixed basal and classical features. Trefoil factor family members were upregulated in classical populations, while the basal populations showed enhanced expression of mesenchymal genes, including VIM and IGTB1. Acinar-ductal metaplasia (ADM) populations, present in 95% of patients, with 46% reduction of driver mutation fractions compared to tumor populations, exhibited suppressive and oncogenic features linked to morphologic states. We identified coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin receptor expression in tumor cells. Higher expression of angiogenic and stress response genes in dendritic cells compared to tumor cells suggests they have a pro-tumorigenic role in remodeling the microenvironment. Treated samples contain a three-fold enrichment of inflammatory CAFs when compared to untreated samples, while other CAF subtypes remain similar. A subset of tumor and/or ADM-specific biomarkers showed differential expression between treatment groups, and several known drug targets displayed potential cross-cell type reactivities. This resolution that spatially defined single cell omics provides reveals the diversity of tumor and microenvironment populations in PDAC. Such understanding may lead to more optimal treatment regimens for patients with this devastating disease. HIGHLIGHTS 1. Acinar-ductal metaplasia (ADM) cells represent a genetic and morphologic transition state between acinar and tumor cells. 2. Inflammatory cancer associated fibroblasts (iCAFs) are a major component of the PDAC TME and are significantly higher in treated samples 3. Receptor-ligand analysis reveals tumor cell-TME interactions through NECTIN4-TIGIT 4. Tumor and ADM cell proteogenomics differ between treated and untreated samples, with unique and shared potential drug targets Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵¶ Lead contact

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Angiogenesis / Cancer / Cancer Biology / Cellular stress response / Dendritic cells / Fibroblasts / Immunoregulation / Inflammation / Lymphocytes T / Mesenchyme / Metabolic response / Metaplasia / Microenvironments / Nectin / Pancreatic cancer / Smad4 protein / Therapeutic targets / Trefoil factor / Tumor cells / Tumors