Single-cell Analysis of Gastric Pre-cancerous and Cancer Lesions Reveals Cell Lineage Diversity and Intratumoral Heterogeneity

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2022 Jan 28

PMID 35087207

Authors

Jihyun Kim

Charny Park

Kwang H Kim

Eun Hye Kim

Hyunki Kim

Jong Kyu Woo

Je Kyung Seong

Ki Taek Nam

Yong Chan Lee

Soo Young Cho

Affiliations

Soon will be listed here.

Abstract

Single-cell transcriptomic profiles analysis has proposed new insights for understanding the behavior of human gastric cancer (GC). GC offers a unique model of intratumoral heterogeneity. However, the specific classes of cells involved in carcinogenetic passage, and the tumor microenvironment of stromal cells was poorly understood. We characterized the heterogeneous cell population of precancerous lesions and gastric cancer at the single-cell resolution by RNA sequencing. We identified 10 gastric cell subtypes and showed the intestinal and diffuse-type cancer were characterized by different cell population. We found that the intestinal and diffuse-type cancer cells have the differential metaplastic cell lineages: intestinal-type cancer cells differentiated along the intestinal metaplasia lineage while diffuse-type cancer cells resemble de novo pathway. We observed an enriched CCND1 mutation in premalignant disease state and discovered cancer-associated fibroblast cells harboring pro-stemness properties. In particular, tumor cells could be categorized into previously proposed molecular subtypes and harbored specific subtype of malignant cell with high expression level of epithelial-myofibroblast transition which was correlated with poor clinical prognosis. In addition to intratumoral heterogeneity, the analysis revealed different cellular lineages were responsible for potential carcinogenetic pathways. Single-cell transcriptomes analysis of gastric pre-cancerous lesions and cancer may provide insights for understanding GC cell behavior, suggesting potential targets for the diagnosis and treatment of GC.

Citing Articles

Antigen-presenting cancer associated fibroblasts enhance antitumor immunity and predict immunotherapy response.

Song J, Wei R, Liu C, Zhao Z, Liu X, Wang Y Nat Commun. 2025; 16(1):2175.

PMID: 40038297 PMC: 11880398. DOI: 10.1038/s41467-025-57465-7.

BTK inhibitors are a possible emerging therapeutic target for gastric cancer.

Portillo-Mino J, Calderon J, Riquelme A Mol Ther Oncol. 2025; 33(1):200935.

PMID: 39990595 PMC: 11846545. DOI: 10.1016/j.omton.2025.200935.

Single-cell profiling reveals a reduced epithelial defense system, decreased immune responses and the immune regulatory roles of different fibroblast subpopulations in chronic atrophic gastritis.

Lin L, Huang T, Li L, Lin Y, Chen F, Zheng Z J Transl Med. 2025; 23(1):159.

PMID: 39905493 PMC: 11796052. DOI: 10.1186/s12967-025-06150-w.

Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects.

Cao Z, Quazi S, Arora S, Osellame L, Burvenich I, Janes P J Biomed Sci. 2025; 32(1):7.

PMID: 39780187 PMC: 11715488. DOI: 10.1186/s12929-024-01099-2.

Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Based on EcoTyper Machine Learning Framework Identifies Cell-State-Specific M2 Macrophage Markers Associated with Gastric Cancer Prognosis.

Zhu A, Li G, Chen F, Shan J, Shan Y, Lv C Immunotargets Ther. 2024; 13:721-734.

PMID: 39678138 PMC: 11646439. DOI: 10.2147/ITT.S490075.

References

Correa P . Gastric cancer: two epidemics?. Dig Dis Sci. 2011; 56(5):1585-6. DOI: 10.1007/s10620-011-1642-x. View

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M . Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001; 345(11):784-9. DOI: 10.1056/NEJMoa001999. View

Cristescu R, Lee J, Nebozhyn M, Kim K, Ting J, Wong S . Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015; 21(5):449-56. DOI: 10.1038/nm.3850. View

Huang K, Ramnarayanan K, Zhu F, Srivastava S, Xu C, Tan A . Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer. Cancer Cell. 2018; 33(1):137-150.e5. DOI: 10.1016/j.ccell.2017.11.018. View

Boussioutas A, Li H, Liu J, Waring P, Lade S, Holloway A . Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res. 2003; 63(10):2569-77. View

Bockerstett K, Lewis S, Wolf K, Noto C, Jackson N, Ford E . Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach. Gut. 2019; 69(6):1027-1038. PMC: 7282188. DOI: 10.1136/gutjnl-2019-318930. View

Zeng D, Li M, Zhou R, Zhang J, Sun H, Shi M . Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures. Cancer Immunol Res. 2019; 7(5):737-750. DOI: 10.1158/2326-6066.CIR-18-0436. View

Zhang P, Yang M, Zhang Y, Xiao S, Lai X, Tan A . Dissecting the Single-Cell Transcriptome Network Underlying Gastric Premalignant Lesions and Early Gastric Cancer. Cell Rep. 2019; 27(6):1934-1947.e5. DOI: 10.1016/j.celrep.2019.04.052. View

10.

Zhang M, Hu S, Min M, Ni Y, Lu Z, Sun X . Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing. Gut. 2020; 70(3):464-475. PMC: 7873416. DOI: 10.1136/gutjnl-2019-320368. View

11.

Sathe A, Grimes S, Lau B, Chen J, Suarez C, Huang R . Single-Cell Genomic Characterization Reveals the Cellular Reprogramming of the Gastric Tumor Microenvironment. Clin Cancer Res. 2020; 26(11):2640-2653. PMC: 7269843. DOI: 10.1158/1078-0432.CCR-19-3231. View

12.

Wang R, Dang M, Harada K, Han G, Wang F, Pizzi M . Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma. Nat Med. 2021; 27(1):141-151. PMC: 8074162. DOI: 10.1038/s41591-020-1125-8. View

13.

Klebanoff C, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones A, Finkelstein S . Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A. 2005; 102(27):9571-6. PMC: 1172264. DOI: 10.1073/pnas.0503726102. View

14.

Zhang R, Li F, Li H, Yu J, Ren X . The clinical significance of memory T cells and its subsets in gastric cancer. Clin Transl Oncol. 2013; 16(3):257-65. DOI: 10.1007/s12094-013-1066-5. View

15.

Qiu X, Hill A, Packer J, Lin D, Ma Y, Trapnell C . Single-cell mRNA quantification and differential analysis with Census. Nat Methods. 2017; 14(3):309-315. PMC: 5330805. DOI: 10.1038/nmeth.4150. View

16.

Lee H, Nam K, Park H, Kim M, LaFleur B, Aburatani H . Gene expression profiling of metaplastic lineages identifies CDH17 as a prognostic marker in early stage gastric cancer. Gastroenterology. 2010; 139(1):213-25.e3. PMC: 2917327. DOI: 10.1053/j.gastro.2010.04.008. View

17.

Jinawath N, Furukawa Y, Hasegawa S, Li M, Tsunoda T, Satoh S . Comparison of gene-expression profiles between diffuse- and intestinal-type gastric cancers using a genome-wide cDNA microarray. Oncogene. 2004; 23(40):6830-44. DOI: 10.1038/sj.onc.1207886. View

18.

Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M . A model for gastric cancer epidemiology. Lancet. 1975; 2(7924):58-60. DOI: 10.1016/s0140-6736(75)90498-5. View

19.

Chiurillo M . Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med. 2015; 5(2):84-102. PMC: 4436943. DOI: 10.5493/wjem.v5.i2.84. View

20.

Tanabe S, Aoyagi K, Yokozaki H, Sasaki H . Gene expression signatures for identifying diffuse-type gastric cancer associated with epithelial-mesenchymal transition. Int J Oncol. 2014; 44(6):1955-70. DOI: 10.3892/ijo.2014.2387. View