Abstract 6227: Cancer-associated enteric glial cell abundance as a prognostic marker in gastric cancer revealed by single-cell analysis

Cancer Research · 2026-04-03

Abstract Enteric glial cells (EGCs), essential regulators of gastrointestinal barrier function, immune responses, and neuro-epithelial homeostasis, remain largely unexplored in the context of gastric cancer (GC). EGCs are a specialized population of peripheral neuroglia that, along with enteric neurons, make up the enteric nervous system. While neural innervation in GC has been increasingly recognized, the presence and functional significance of cancer-associated EGCs (CAEGCs) within the gastric tumor microenvironment (TME) remain undefined. In this study, we utilized integrative single-cell transcriptomic analysis of human GC to identify a rare but distinct population of CAEGCs residing within the stromal compartment. Defined by consistent expression of canonical glial markers, this CAEGC population emerged as a robust and reproducible signature across six independent datasets. To evaluate clinical relevance, we then applied LASSO-Cox regression modeling to The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort to establish a GAEGC-derived glial signature that stratified GC patients into high- and low-risk groups with significant survival differences (p < 0.001) and distinct molecular features. This GAEGC-derived glial signature also aligned with established molecular subtypes and predicted response to therapy. Our findings reveal a prognostically relevant and previously underappreciated population of CAEGC-like stromal cells within the GC TME. This GAEGC-derived glial signature offers a way to predict GC relapse risk and survival, and it highlights neuro-glial interactions as a potential site of therapeutic intervention in GC. Citation Format: Carolyn R. DePinho, Jianming Zeng, Xiling SHEN, Sandra W. Ryeom. Cancer-associated enteric glial cell abundance as a prognostic marker in gastric cancer revealed by single-cell analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6227.

Single-nucleus multiome sequencing identifies candidate regulators of mouse gastric epithelial homeostasis

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-27

Abstract Background & Aims Gastric epithelial cells maintain homeostasis through dynamic self-renewal mechanisms involving stem and progenitor cells; however, identifying them has been challenging. This study aims to identify stem cells of healthy gastric epithelium and cell type-specific regulators defining gastric epithelial homeostasis via single-nucleus multiome analysis. Methods Ten unique gastric samples were collected from 8-12 week old wildtype mice. Isolated nuclei were subjected to simultaneous profiling of gene expression and chromatin accessibility. After quality control, 31,598 cells were analyzed with Seurat and Signac using weighted-nearest neighbors analysis for joint RNA and ATAC clustering. Furthermore, SCENIC+, MultiVelo, EpiCHAOS and Cell plasticity score were used to uncover gene regulatory networks, cell state dynamics and lineage trajectories. Results Our analyses were validated by the identification of known regulators of stem-cell differentiation into mature cell types. More importantly, it revealed previously uncharacterized regulatory networks comprising novel transcription factor combinations that define cell identities, including Ppara , Pparg , Arid5b and Sox5 as candidate regulators of parietal, foveolar, chief and neck cells, respectively. Further, our data support the identity of isthmus cells as stem-like cells of healthy gastric epithelium, as evidenced by epigenetic plasticity that simultaneously contains open chromatin states of all differentiated cell types in the absence of transcriptional reprogramming. Conclusion Consistent with Waddington’s epigenetic landscape hypothesis, gastric epithelial homeostasis is controlled by orchestrated epigenetic and transcriptional programs. Contrary to the prevailing hypothesis, stem cells can be defined not by a separate epigenetic state but by epigenetic superposition of differentiated cell states. Future work is needed to define the universality of these results.

Editorial Expression of Concern: Nociceptive neurons promote gastric tumour progression via a CGRP–RAMP1 axis

Nature · 2026-05-05

Abstract 7479: A CCL20-high chemokine program defines a CCR6+ immune-myeloid niche in gastric cancer

Cancer Research · 2026-04-03

Abstract Introduction: Gastric cancer remains one of the leading causes of cancer mortality worldwide and is characterized by an aggressive clinical course and a profoundly immunosuppressive tumor microenvironment with limited therapeutic options. Chemokine signaling has emerged as an important regulator of gastric tumor progression, and among these pathways, the CCL20-CCR6 axis is a validated driver of epithelial to mesenchymal transition, invasion, and metastasis, and is associated with poor patient survival. However, the upstream signals that generate high levels of CCL20 within gastric tumors, and the specific CCR6+ immune compartment that respond to this signal remain poorly understood. Understanding the source and downstream signaling for this axis may offer novel therapeutic options for gastric cancer. Here, we identify a previously unrecognized CCL20 high chemokine signature and a dynamically regulated CCR6+ immune and myeloid niche in gastric cancer. Methods: Chemokine profiling of murine gastric cancer cell lines, multiplex immunohistochemistry of gastric tumors isolated from preclinical models of gastric cancer, and integration with human gastric single-cell RNA-seq confirmed CCL20 expression by gastric cancer cells and CCR6 expression in myeloid and B lineage clusters in the gastric tumor microenvironment. Results: Gastric cancer murine organoids exhibited a distinct chemokine signature marked by high CCL20 together with CCL22 and M-CSF. Confocal imaging confirmed abundant CCL20 protein within gastric tumors and organoids. Analysis of TCGA stomach adenocarcinoma data demonstrated that high CCR6 expression correlates with reduced overall survival. Multiplex immunohistochemistry revealed that substantial CCR6 positive CD11c+ MHCII+ immune cells infiltrate into the gastric cancer tumor microenvironment, including B220+ plasmacytoid DC-like (pDC-like) subset. pDC-like cells increased with tumor burden and was modulated by anti-PD-1 and 5-fluorouracil treatment, indicating dynamic regulation of CCR6+ myeloid subsets. Human gastric single-cell RNA-seq datasets identified CCR6 expression on myeloid clusters capable of responding to CCL20 through the CCR6 receptor. Conclusions: These findings define a previously unrecognized CCL20-high, CCR6+ immune-myeloid population in gastric cancer that offers insight into the source of chemokines that drive recruitment of immune cells into the gastric cancer tumor microenvironment. Targeting this axis may reveal actionable vulnerabilities in gastric cancer progression. Citation Format: Kurtay Ozuner, Jaewon Kim, Sandra W. Ryeom. A CCL20-high chemokine program defines a CCR6+ immune-myeloid niche in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7479.

Lung endothelial niche signaling governs self-renewal and fate transitions of human alveolar stem cells

bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-09

Abstract Chronic lung diseases such as pulmonary fibrosis are characterized by the irreversible loss of alveolar type 1 (AT1) cells, yet the mechanisms governing human alveolar stem cell self-renewal and differentiation remain poorly defined. Here, we identify a lung endothelial niche that sustains the self-renewal of human alveolar type 2 (AT2) stem cells through MAPK signaling, enabling robust long-term expansion while preserving stem cell fate. Although YAP activation initiates AT1 transcriptional programs, it is insufficient to complete lineage maturation. We show that MAPK inhibition together with LATS inhibition promotes nuclear translocation of YAP, enhancing AT1 differentiation. Expanded human AT2 stem cells engraft in fibrotic lungs and contribute to alveolar regeneration while undergoing directed differentiation within diseased human lung tissue. Together, our findings define a niche-controlled signaling mechanism governing human alveolar stem cell fate and advance our understanding of alveolar regeneration.

Electroporation-Induced Gastric Cancer Models Through Epithelial-Specific Genetic Modifications

Gastro Hep Advances · 2026-01-01

Retraction notice to “Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma” Int J Radiat Oncol Biol Phys, 2009; 74(4), pp 1207-1216

International Journal of Radiation Oncology*Biology*Physics · 2025-05-15

Strengthening Asian/Asian American, Native Hawaiian, and Pacific Islander Leadership in Cancer Research

Cancer Discovery · 2025-02-07 · 2 citations

Individuals in the United States from Asian and Asian American, Native Hawaiian, and Pacific Islander (AANHPI) backgrounds face a distinct set of cancer-related disparities. In this study, in conjunction with the American Association for Cancer Research Asian/AANHPI Task Force, we highlight the unique disparities faced by AANHPI patients and professionals, and we offer actionable recommendations on how to strengthen AANHPI leadership in cancer research.

Su1191: TUMOR-ASSOCIATED CATHEPSIN EXPRESSION IS A NOVEL BIOMARKER IN A FIRST–IN-HUMAN CLINICAL TRIAL OF PEGULICIANINEFLUORESCENCE FOR INTERCEPTION OF GASTROESOPHAGEAL CANCERS

Gastroenterology · 2025-05-01

Abstract 4385: Preclinical evaluation of RAS pathway inhibitors in gastroesophageal adenocarcinoma

Cancer Research · 2025-04-21

Abstract Gastric cancer is the 4th leading cause of cancer-related deaths worldwide and up to 25% are driven by alterations in the RAS pathway. RAS activation in cancer is commonly a result of a mutation locking the protein in the ON state. However, KRAS amplification (KRASAMP), defined as >6 copies of wild type KRAS allele, occurs more frequently in gastroesophageal adenocarcinoma (GEA). Western blot analysis revealed differences in MAPK signaling amplitude between KRASAMP and KRASMUT cell lines after synchronization. KRASAMP cells show a sharp spike in signaling upon stimulation, followed by attenuation, we speculate due to negative feedback. Historically KRASAMP has been difficult to target due to adaptive signaling requiring MAPK inhibition at multiple signaling nodes, yet these combinations are clinically limited by toxicity. Here we test novel RAS pathway inhibitors in KRASAMP/MUT GEA cell lines, to investigate toxicity, synergy with drug combinations, and efficacy of MAPK pathway target inhibition by quantifying levels of p-ERK. KRASAMP GEA cells ranged in copy number from 8-68; while all GEA mutant cell lines harbored KRASG12D mutations. GEA cells were seeded in 96 well plates, treated with drug for 5 days then assessed for viability via Cell titer glo. The half-maximal effective drug concentration (EC50) for p-ERK inhibition was determined by Western blot analysis after 24 hours of drug treatment. The pan-KRAS (OFF) Inhibitor, BI-2865 inhibits KRAS altered GEA cell viability with an IC50 ranging from 0.2 - 1.4 μM in KRASAMP and KRASG12D mutant cell lines. The RAF/MEK clamp VS-6766 demonstrated an IC50 range from 0.81 μM in KRASAMP in cell lines, while mutant KRASG12D lines exhibited 40-fold lower sensitivity. The allosteric SHP2 inhibitor RMC-4550 demonstrated an IC50 of 0.08-6.67 μM in KRASAMP and KRASG12D lines. BI-2865 suppressed p-ERK protein expression with an EC50 of 16 and 45 nM in KRASAMP and KRASMUT GEA cells respectively. There was no adaptive signaling through PI3K pathways based on suppressed p-AKT levels, in comparison to trametinib which resulted in increases in pAKT. The RAF/MEK clamp VS-6766 also inhibits signaling through MAPK as evidenced by decreased p-AKT, and an EC50 for p-ERK of 131.83 nM (KRASAMP) and 10.4725 nM (KRASMUT) GEA cells. Our data indicates a positive correlation between KRAS copy number and the IC50 of RAS-MAPK pathway inhibitors, suggesting cells with more KRAS copies require higher doses to achieve cytotoxicity; this is also reflected in the dose required for target engagement. This highlights the differential sensitivity of KRASAMP versus mutant cell lines, emphasizing the complexity of KRASAMP tumors and their reliance on high copy numbers. Our results suggest that combination strategies will be essential to overcome adaptive resistance and maximize therapeutic benefit in KRASAMP cells. Future in vivo studies will validate the potential of these inhibitors and combination approaches. Citation Format: Zachary Hammer, Jack Rifkin, Ralph Fleuranvil, Babita Pokharel, Stella Savone, Sandra W. Ryeom, Mariam El-Ashmawy. Preclinical evaluation of RAS pathway inhibitors in gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4385.