Ni R, Dong H, Han RD, Ren XC, Qu YL, Wang L, Chen SS, Zhang YC. Spatial transcriptomics reveals tumor niche heterogeneity in advanced gastric cancer and suggests a tumor-promoting role for KRT6B. World J Gastrointest Oncol 2026; 18(9): 121446 [DOI: 10.4251/wjgo.121446]
Corresponding Author of This Article
You-Cheng Zhang, MD, PhD, Professor, Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Second Hospital and Clinical Medical School, Lanzhou University, No. 82 Cuiying Gate, Chengguan District, Lanzhou 730030, Gansu Province, China. zhangychmd@126.com
Research Domain of This Article
Oncology
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research-article
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Ni R, Dong H, Han RD, Ren XC, Qu YL, Wang L, Chen SS, Zhang YC. Spatial transcriptomics reveals tumor niche heterogeneity in advanced gastric cancer and suggests a tumor-promoting role for KRT6B. World J Gastrointest Oncol 2026; 18(9): 121446 [DOI: 10.4251/wjgo.121446]
Rui Ni, Xue-Chen Ren, You-Cheng Zhang, Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
Hui Dong, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Rui-Dong Han, Lei Wang, Shen-Si Chen, Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Yu-Ling Qu, Department of Pathology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Co-first authors: Rui Ni and Hui Dong.
Co-corresponding authors: Shen-Si Chen and You-Cheng Zhang.
Author contributions: Ni R drafted the manuscript and acquired funding; Ni R and Dong H designed the study methodology as co-first authors; Dong H contributed to methodology development and data curation; Han RD, Qu YL, and Wang L performed validation; Ren XC conducted software analysis and data curation; Chen SS administered the project, supervised the research, and acquired funding; Chen SS and Zhang YC conceived the study as co-corresponding authors; Zhang YC reviewed and revised the manuscript, supervised the research, and administered the project; all authors read and approved the final manuscript.
Supported by Natural Science Foundation project of Ningxia, No. 2023AAC03680; and Ningxia Medical University Research Project, No. XM2020166.
Institutional review board statement: This study was reviewed and approved by the Scientific Research Ethics Committee of the General Hospital of Ningxia Medical University (approval No. KYLL-2022-0710).
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Data sharing statement: The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive for Human in the National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences, under accession number HRA013687, and are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.
Corresponding author: You-Cheng Zhang, MD, PhD, Professor, Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Second Hospital and Clinical Medical School, Lanzhou University, No. 82 Cuiying Gate, Chengguan District, Lanzhou 730030, Gansu Province, China. zhangychmd@126.com
Received: March 26, 2026 Revised: April 17, 2026 Accepted: June 2, 2026 Published online: September 15, 2026 Processing time: 154 Days and 5.9 Hours
Abstract
BACKGROUND
Gastric cancer (GC) is highly heterogeneous, which complicates its diagnosis and treatment. Although single-cell transcriptomic approaches can characterize cellular heterogeneity, they do not preserve spatial information. They therefore cannot adequately resolve spatial heterogeneity within tumors. We hypothesized that full-thickness spatial transcriptomic profiling would reveal intratumoral spatial heterogeneity and identify distinct tumor niches in advanced GC (AGC).
AIM
To characterize intratumoral spatial heterogeneity and identify distinct tumor niches in AGC.
METHODS
Full-thickness AGC tissues were profiled using Stereo-seq. Spatial niches were identified using BANKSY, expression trends were analyzed using Mfuzz, and niche-specific signaling was assessed through ligand-receptor analysis. Functional programs were evaluated using gene set enrichment analysis, gene set variation analysis, and enrichment analysis of differentially expressed genes. KRT6B was assessed by immunofluorescence, immunohistochemistry, analysis of public datasets, and survival analysis, and its function was examined in KRT6B-overexpressing GC cells using proliferation, migration, and invasion assays.
RESULTS
We identified 13 spatial niches, demonstrating marked intratumoral spatial heterogeneity. Three tumor-dominant niches (N5, N4, and N2) formed a superficial-to-deep axis and exhibited graded transcriptional programs, with stronger stemness-related and motility-related features in superficial regions and increased immune-related and metabolism-related programs in deeper regions, along with niche-specific intercellular signaling patterns. We also identified a spatially isolated tumor nest (N9) with relatively stronger transcriptional features for proliferation, metabolism, and immune/inflammation, and preferential enrichment for KRT6B. KRT6B was enriched in tumor nests and at the invasive front, upregulated in GC tissues, and associated with poor prognosis. In vitro, KRT6B overexpression promoted GC cell proliferation, migration, and invasion.
CONCLUSION
Full-thickness spatial transcriptomics revealed marked heterogeneity in AGC and implicated KRT6B as a candidate tumor-promoting molecule for further investigation.
Core Tip: The spatial organization of advanced gastric cancer remains insufficiently characterized. Using full-thickness Stereo-seq profiling, this study identified a superficial-to-deep tumor niche axis, niche-specific transcriptional gradients, and a spatially isolated tumor nest with preferential enrichment for KRT6B. External validation and in vitro assays further supported KRT6B as a candidate molecule associated with aggressive tumor phenotypes. Although the study was based on a limited number of samples, these findings provide an initial spatial framework for investigating intratumoral heterogeneity in advanced gastric cancer.
