FAT4 restrains epithelial-mesenchymal transition and metastasis in cervical cancer and shapes the tumor immune microenvironment

Sep 22, 2026

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Metastatic dissemination drives mortality in cervical cancer, and FAT4—an atypical cadherin upstream of Hippo signaling—has been linked to tumor suppression, though its clinical and mechanistic roles in metastasis remain unclear. Using FAT4 expression profiling in paired patient tissues, immune landscape characterization by mass cytometry, and CRISPR activation to establish causality, the study tests effects on EMT, migration/invasion, and tumor spread in vivo. FAT4 activation suppresses EMT programs and remodels the tumor immune microenvironment, supporting biomarker and therapeutic potential for metastasis control.

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Wang et al. Journal of Translational Medicine (2026) 24:654 [https://doi.org/10.1186/s12967-026-08177-z](https://doi.org/10.1186/s12967-026-08177-z) Journal of Translational Medicine RESEARCH Open Access FAT4 restrains epithelial-mesenchymal transition and metastasis in cervical cancer and shapes the tumor immune microenvironment Dongying Wang1, Shuying Wu1, Hongxin Wang1, Beijia Yan1, Yuxuan Zhang2, Jiaxing He 1 and Tianmin Xu1* Abstract Background Metastatic dissemination remains the major cause of mortality in cervical cancer. FAT4, an atypical cadherin upstream of Hippo signaling, has been implicated in tumor suppression, yet its clinical relevance and mechanistic role in cervical cancer metastasis are insufficiently defined. Methods We assessed FAT4 expression by immunohistochemistry in 40 paired cervical cancer and adjacent tissues and analyzed clinicopathological associations. The immune landscape of 10 freshly resected tumors was profiled using mass cytometry (CyTOF) . To interrogate causality, we activated endogenous FAT4 using CRISPR activation (dCas9-SAM) in cervical cancer cell lines, followed by migration/invasion assays and EMT marker analyses. Metastatic potential was evaluated in xenograft and syngeneic mouse models. Results FAT4 expression was reduced in tumors compared with matched non-tumor tissues and aligned with metastatic features. CyTOF delineated distinct immune compositions between FAT4-high and FAT4-low tumors, indicating a remodeled tumor immune microenvironment. CRISPRa-mediated FAT4 activation curtailed cell migration and invasion, restored epithelial markers, and suppressed mesenchymal markers, consistent with epithelialmesenchymal transition (EMT) restraint. In vivo, enforced FAT4 reduced metastatic burden. Mechanistically, FAT4 activation was associated with suppression of EMT transcriptional programs and with signaling signatures consistent with reduced PI3K–AKT/Wnt/Hippo pathway signatures. Conclusions FAT4 acts as a metastasis suppressor in cervical cancer by constraining EMT and remodeling the tumor immune microenvironment. These data support FAT4 as a potential biomarker and therapeutic entry point for metastasis control. Highlights • FAT4 is frequently downregulated in cervical cancer and is associated with aggressive clinicopathologic features. *Correspondence: Tianmin Xu [xutianmin@126.com](xutianmin@126.com) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Wang et al. Journal of Translational Medicine (2026) 24:654 Page 2 of 15 • FAT4 activation reverses epithelial–mesenchymal transition and suppresses cervical cancer cell migration and invasion in vitro. • FAT4 activation reduces metastatic burden, restrains tumor progression, and prolongs survival in mouse models. • FAT4-high tumors exhibit a lymphocyte

FAQs

What is the main role of FAT4 in cervical cancer progression?

FAT4 acts as a metastasis suppressor by constraining epithelial-mesenchymal transition (EMT) and remodeling the tumor immune microenvironment.

How was FAT4 linked to patient tissues and clinical features?

FAT4 expression was assessed by immunohistochemistry in 40 paired cervical cancer and adjacent tissues, followed by analysis of clinicopathological associations.

What experimental approach established a causal relationship between FAT4 and metastatic behavior?

Endogenous FAT4 was activated in cervical cancer cell lines using CRISPR activation (dCas9-SAM), with subsequent migration/invasion assays, EMT marker analysis, and evaluation in xenograft and syngeneic mouse models.

Sep 22, 2026

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