YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis

Cancer Heterogeneity and Plasticity 2026;3(1):0003 | https://doi.org/10.47248/chp2603010003

Original Research Open Access

YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis

Jingjing Wu ^1,2 , Dipti Athavale ^3,4 , Curt Balch ^3,4 , Junsong Zhao ^3,4 , Gengyi Zou ¹ , Yibo Fan ¹ , Yanting Zhang ^3,4,5 , Joseph Zhao ⁶ , Mikel Ghelfi ^3,4 , Anthony Pompetti ^3,4 , Gennaro Calendo ^3,4 , Ailing Scott ¹ , Shan Shao ¹ , Xiaodan Yao ^3,4 , Melissa Pool Pizzi ¹ , Christopher Vellano ⁷ , Vladimir Khazak ⁸ , Sheng Zhang ² , Timothy A Yap ⁹ , Shilpa S Dhar ¹ , Raghav Sundar ⁶ , Francis Spitz ^4,5,10 , Generosa Grana ^4,10 , Jaffer A. Ajani ¹ , Shumei Song ^3,4,5,10,11

1. Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2. Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
3. Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ, 08103, USA
4. Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ, 08103, USA
5. Departments of Biomedical Sciences and Surgery, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ, 08103, USA
6. Department of Medicine, Yale School of Medicine and Yale Cancer Center, PO Box 208028, New Haven, CT 06520-8028, USA
7. Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
8. NexusPharma Inc. 17 Black Forest Road, Hamilton, NJ 08691, USA
9. Department of Investigational Cancer Therapeutics (Phase 1 program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
10. MD Anderson Cancer Center at Cooper, Cooper University Hospital, 2 Cooper Plaza, Camden, NJ, 08103, USA
11. Department of Cancer Pharmacology, Rutgers Cancer Institute, 195 Little Albany St, New Brunswick, NJ 08901, USA

Correspondence: Jaffer A. Ajani; Shumei Song

Academic Editor(s): Dean G. Tang

Received: Jan 16, 2026 | Accepted: Mar 17, 2026 | Published: Mar 28, 2026

Cite this article: Wu J, Athavale D, Balch C, Zhao J, Zou G, Fan Y, Zhang Y, Zhao J, Ghelfi M, Pompetti A, Calendo G, Scott A, Shao S, Yao X, Pizzi MP, Vellano C, Khazak V, Zhang S, Yap TA, Dhar SS, Sundar R, Spitz F, Grana G, Ajani JA, Song S. YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis. Cancer Heterog Plast. 2026;3(1):0003. https://doi.org/10.47248/chp2603010003

Abstract

Background: Dysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumor progression, immunosuppression, and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumors, however, the expression profiles of Hippo coactivators YAP1, TAZ, and their transcriptional factors TEAD1-4 in gastric cancer peritoneal metastases (GCPMs), and their therapeutic value, are unknown. In this study, we sought to determine the expression status of YAP1, TAZ, and TEAD1-4 in GCPMs and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumor activity compared with inhibition of either coactivator alone.

Methods: Expression of YAP1, TAZ, and TEAD1–4 was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects in vitro and in vivo. Co-immunoprecipitation and luciferase reporter assays were used to characterize YAP1/TAZ interactions with TEADs and AP-1 components (JUN and FOSB) and to quantify transcriptional activity. Antitumor efficacy was validated in patient-derived xenograft (PDX) and KP-Luc2 syngeneic models.

Results: YAP1, TAZ, and TEADs1-4 were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion in vitro, and tumor growth in vivo. Increased TAZ complexation with TEAD4 and AP-1 (c-JUN and FOSB) heterodimer was observed following YAP1 knockdown or pharmacological ASO inhibition. Dual inhibition of YAP1 and TAZ was required to maximally suppress YAP1/TAZ expression and reduce their nuclear accumulation, transactivation of TEAD, and activation of downstream genes.

Conclusions: These findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPM, a highly lethal disease with an urgent need for novel treatment options.

Keywords

Antisense oligonucleotide (ASO), gastric cancer peritoneal metastasis (GCPM), Hippo pathway, YAP1, TAZ, TEAD1-TEAD4, targeted therapy

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