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Peer-reviewedCC BY 4.0Journal of Biomedical Science

Stromal CCL2/CXCL10/SPARC axes drive pro-tumor CHI3L1 expression for microenvironmental modulation in pancreatic cancer progression and therapeutic innovation

  • Pei-Chia Su1
  • Yan-Shen Shan2,3
  • Ya-Chin Hou2,3
  • Po-Hsien Huang4
  • Pao-Chi Liao5
  • Yi-Ching Wang1,6
6 affiliations
  1. 1Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, Ta-Hsueh Road, Tainan, 70101 Taiwan
  2. 2Department of Clinical Medical Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  3. 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  4. 4Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  5. 5Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  6. 6Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Abstract

Background: Chitinase-3-like-protein 1 (CHI3L1), a low-abundance protein in normal tissues, is markedly upregulated in the pancreatic tumor microenvironment (TME), where it promotes fibrosis and immune evasion. Spatial transcriptomics revealed enrichment of CHI3L1 at tumor-stroma interfaces, suggesting that cell-cell interactions regulate CHI3L1 expression.

Methods: We employed 2D and 3D multicellular culture models, incorporating pancreatic cancer cells, macrophages, and pancreatic stellate cells (PSCs), to recapitulate TME-mediated CHI3L1 induction. Mechanistic insights were gained through secretome profiling, chromatin immunoprecipitation (ChIP), and methylation-specific PCR. The therapeutic potential of targeting identified axes was evaluated in an orthotopic pancreatic adenocarcinoma (PDAC) mouse model.

Results: We identified CCL2, CXCL10, and SPARC as key secreted mediators during tumor-stroma crosstalk that cooperatively induced CHI3L1 expression in cancer cells via activation of NF-κB and STAT3. Specifically, inflammatory cytokines within the TME recruited macrophages to induce CCL2, which, in concert with PSCs, enhances CXCL10 and SPARC secretion. Mechanistically, NF-κB directly bound the CHI3L1 promoter, while STAT3 reduced DNA methyltransferase 1 levels, leading to promoter hypomethylation and epigenetic activation of CHI3L1. Clinically, high CHI3L1 expression correlated with the upregulated stromal CCL2, CXCL10, and SPARC levels, and the combined four-marker signature was an independent prognostic factor for both overall and disease-free survival in multivariable analysis. In vivo, blockade of the upstream stromal pathways (CCR2/CXCR3/TGFβR1) coupled with CHI3L1 neutralization reduced tumor growth and remodeled the immunosuppressive microenvironment in immunocompetent PDAC models.

Conclusions: Our findings uncover a cooperative multicellular signaling network that orchestrates CHI3L1 expression in cancer via transcriptional and epigenetic reprogramming. Disrupting these upstream stromal pathways concurrently with CHI3L1 neutralization was associated with reduced T-cell exhaustion, offering a promising combinatorial approach for PDAC immunotherapy.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12929-026-01295-2.

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Cite

BibTeXRIS
BibTeX
@article{su2026stromal,
  title = {{Stromal CCL2/CXCL10/SPARC axes drive pro-tumor CHI3L1 expression for microenvironmental modulation in pancreatic cancer progression and therapeutic innovation}},
  author = {Pei-Chia Su and Yan-Shen Shan and Ya-Chin Hou and Po-Hsien Huang and Pao-Chi Liao and Yi-Ching Wang},
  journal = {Journal of Biomedical Science},
  year = {2026},
  month = oct,
  doi = {10.1186/s12929-026-01295-2},
  url = {https://doi.org/10.1186/s12929-026-01295-2},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Stromal CCL2/CXCL10/SPARC axes drive pro-tumor CHI3L1 expression for microenvironmental modulation in pancreatic cancer progression and therapeutic innovation
AU  - Pei-Chia Su
AU  - Yan-Shen Shan
AU  - Ya-Chin Hou
AU  - Po-Hsien Huang
AU  - Pao-Chi Liao
AU  - Yi-Ching Wang
PY  - 2026
DA  - 2026/10/26
JO  - Journal of Biomedical Science
DO  - 10.1186/s12929-026-01295-2
UR  - https://doi.org/10.1186/s12929-026-01295-2
AB  - Background: Chitinase-3-like-protein 1 (CHI3L1), a low-abundance protein in normal tissues, is markedly upregulated in the pancreatic tumor microenvironment (TME), where it promotes fibrosis and immune evasion. Spatial transcriptomics revealed enrichment of CHI3L1 at tumor-stroma interfaces, suggesting that cell-cell interactions regulate CHI3L1 expression.  Methods: We employed 2D and 3D multicellular culture models, incorporating pancreatic cancer cells, macrophages, and pancreatic stellate cells (PSCs), to recapitulate TME-mediated CHI3L1 induction. Mechanistic insights were gained through secretome profiling, chromatin immunoprecipitation (ChIP), and methylation-specific PCR. The therapeutic potential of targeting identified axes was evaluated in an orthotopic pancreatic adenocarcinoma (PDAC) mouse model.  Results: We identified CCL2, CXCL10, and SPARC as key secreted mediators during tumor-stroma crosstalk that cooperatively induced CHI3L1 expression in cancer cells via activation of NF-κB and STAT3. Specifically, inflammatory cytokines within the TME recruited macrophages to induce CCL2, which, in concert with PSCs, enhances CXCL10 and SPARC secretion. Mechanistically, NF-κB directly bound the CHI3L1 promoter, while STAT3 reduced DNA methyltransferase 1 levels, leading to promoter hypomethylation and epigenetic activation of CHI3L1. Clinically, high CHI3L1 expression correlated with the upregulated stromal CCL2, CXCL10, and SPARC levels, and the combined four-marker signature was an independent prognostic factor for both overall and disease-free survival in multivariable analysis. In vivo, blockade of the upstream stromal pathways (CCR2/CXCR3/TGFβR1) coupled with CHI3L1 neutralization reduced tumor growth and remodeled the immunosuppressive microenvironment in immunocompetent PDAC models.  Conclusions: Our findings uncover a cooperative multicellular signaling network that orchestrates CHI3L1 expression in cancer via transcriptional and epigenetic reprogramming. Disrupting these upstream stromal pathways concurrently with CHI3L1 neutralization was associated with reduced T-cell exhaustion, offering a promising combinatorial approach for PDAC immunotherapy.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12929-026-01295-2.
SN  - 1021-7770
SN  - 1423-0127
ER  -