PLPP4 marks a fibroblast subset that fuels tumor growth through excess matrix deposition

Cancer-associated fibroblasts, the main cellular producers of extracellular matrix within the tumor microenvironment, vary widely in how much matrix they make, and researchers have lacked definitive markers for the most prolific subset. A new study published in the Journal of Experimental & Clinical Cancer Research identifies the lipid-processing enzyme PLPP4 as a functional marker of an extracellular-matrix-enriched fibroblast subset and traces the molecular circuitry through which these cells drive tumor growth and metastasis.

The team, led by Shubin Yu, Huiya Xu and Boxuan Zhou with senior author Jianming Li, used integrated single-cell RNA sequencing to stratify fibroblast subsets and pinpoint subset-specific membrane markers. They then tested the functions of those markers with gain- and loss-of-function assays, mapping protein localization and matrix accumulation with immunohistochemistry, immunofluorescence, Masson’s trichrome and Sirius Red staining.

Functionally, PLPP4 drove tumor growth and metastasis both in vitro and in vivo by promoting excessive deposition of extracellular matrix. The evidence came from a battery of models: spheroid outgrowth assays and co-cultures of patient-derived organoids with fibroblasts in the laboratory, plus syngeneic, xenograft and intrasplenic liver metastasis mouse models in animals.

The mechanism centers on ceramide, a lipid that PLPP4 generates through its phospholipid phosphatase activity. According to the study, ceramide acts through two coordinated routes. In the first, ceramide enables AMPK-mediated phosphorylation and the subsequent nuclear import of ACSS2, expanding the nuclear pool of acetyl coenzyme A. That surplus fuels enhanced H3K27ac histone modification at the promoter regions of matrix-related genes, easing their transcription.

In the second route, ceramide promotes the activation of CREB3L1, a transcription factor that governs the expression of multiple extracellular matrix genes. Together, the authors report, these two pathways push matrix genes—including COL1A1, COL1A2 and fibronectin-1—into excessive expression, thickening the fibrous scaffold that surrounds tumor cells.

The study also uncovered a metabolic trigger: PLPP4 expression rises in fibroblasts under glutamine deprivation, and that upregulation depends on ATF4, a transcription factor commonly activated during nutrient stress.

Clinical data added a correlative dimension. In colorectal cancer, high PLPP4 expression correlated with denser extracellular matrix deposition, impaired immune cell infiltration and unfavorable patient prognosis. The authors validated their findings across pan-cancer and fibrotic tissues using public single-cell RNA sequencing, spatial transcriptomic and clinical databases.

On the basis of these results, the researchers conclude that PLPP4-positive fibroblasts constitute a critical tumor-promoting subset and propose PLPP4 as a promising therapeutic target for anti-cancer strategies. Because the reported clinical associations are correlational, and because the mechanistic work combines cell culture, organoid co-culture and mouse models, translating this target into treatments will require further validation. Readers should also note that the article is being shared ahead of final production as a peer-reviewed, accepted manuscript carrying a permanent DOI; it remains subject to further edits before the final version of record replaces it.

Subject of Research: A cancer-associated fibroblast subset marked by PLPP4 that promotes tumor progression through extracellular matrix deposition

Article Title: PLPP4+ CAFs drive cancer progression by promoting ECM deposition via ceramide-mediated H3K27ac modification and CREB3L1 activation

Article References: Yu, S., Xu, H., Zhou, B., Liu, F., Liu, Q., He, C., Ni, W., Mo, H., Huo, J., Qi, J., Cen, M., He, S., Xu, S., & Li, J. (2026). PLPP4+ CAFs drive cancer progression by promoting ECM deposition via ceramide-mediated H3K27ac modification and CREB3L1 activation. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03850-z

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03850-z

Keywords: cancer-associated fibroblasts, PLPP4, extracellular matrix, ceramide, H3K27ac, CREB3L1, tumor microenvironment, colorectal cancer, single-cell RNA sequencing, metastasis, CAFs, drive