Single‐Cell Transcriptome Analysis Uncovers Intratumoral Heterogeneity and Underlying Mechanisms for Drug Resistance in Hepatobiliary Tumor Organoids

• Published in: Advanced science Vol. 8; no. 11; pp. e2003897 - n/a
• Main Authors: Zhao, Yan, Li, Zhi‐Xuan, Zhu, Yan‐Jing, Fu, Jing, Zhao, Xiao‐Fang, Zhang, Ya‐Ni, Wang, Shan, Wu, Jian‐Min, Wang, Kai‐Ting, Wu, Rui, Sui, Cheng‐Jun, Shen, Si‐Yun, Wu, Xuan, Wang, Hong‐Yang, Gao, Dong, Chen, Lei
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.06.2021; John Wiley and Sons Inc; Wiley
• Subjects: Antigens; Antigens, Neoplasm - genetics; beta Catenin - genetics; Brain cancer; Carbonic Anhydrase IX - genetics; Cell cycle; Cell Cycle Proteins - genetics; Cysts; Digestive System Diseases - drug therapy; Digestive System Diseases - genetics; Digestive System Diseases - pathology; Drug resistance; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - genetics; Fructose-Bisphosphate Aldolase - genetics; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - pathology; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) - genetics; Growth factors; hepatobiliary tumor organoid; Humans; Hyaluronan Receptors - genetics; Intracellular Signaling Peptides and Proteins - genetics; Janus Kinases - genetics; Metastasis; Mutation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Organoids - drug effects; Organoids - metabolism; Organoids - pathology; Patients; Physiology; Principal components analysis; RNA, Long Noncoding - genetics; RNA-Seq; Single-Cell Analysis; STAT Transcription Factors - genetics; Stem cells; Transcriptome - genetics; tumor ecosystem; tumor heterogeneity; Tumors; hepatobiliary tumor organoid; drug resistance; tumor ecosystem; single-cell analysis; tumor heterogeneity
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202003897

Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single‐cell RNA sequencing. HCC272 with high status of epithelia‐mesenchymal transition proves broad‐spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo‐time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta‐1 (CTNNB1), glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak‐STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N‐Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance. The existence of inter‐ and intratumoral heterogeneity is the main cause for tumor drug resistance. Thus, extensive understanding of the underlying mechanism is necessary for developing potential strategy. This study here, for the first time, provides the new understanding for the role of tumor ecosystem involving cell expansion and drug response by applying scRNA‐seq method with tumor organoids.