Therapeutic strategy for cervical gastric-type adenocarcinoma by targeting CLU to relieve CLU-associated stress and sensitize chemotherapy

Abstract

Objectives Gastric-type adenocarcinoma (GAS), an aggressive subtype of non-human papillomavirus (HPV)-associated (NH-PVA) cervical adenocarcinomas (ADC), remains a treatment-refractory disease with poor prognosis. This study aims to explore the oncogenic mechanism and efficacious therapeutic target of GAS.

Methods We included 19 NHPVA and 153 HPVA ADC patients from our center to investigate clinicopathological features. We collected 3 GAS and 2 usual-type endocervical adenocarcinomas (UEA) for single-cell RNA sequencing and T-cell receptor se-quencing. We conducted immunohistochemical staining of 25 GAS and 25 UEA samples and multicolor immunohistochemical staining of 2 GAS samples for validation. We explored the efficacy of anti-clusterin (OGX-011) and/or cisplatin (DDP) for GAS based on GAS-derived tumoroids.

Results Based on clinical data, we clinicopathologically verified the malignancy of GAS. Through single-cell RNA sequencing, we delineated key cell subtypes including GAS epithelial cells, “GAS-enriched fibroblasts”, “GAS-associated γδ T cells”, and CD8 + exhausted T cells enduring heat stress and contributing to GAS aggressive phenotype. Regarding validation, we verified clusterin (CLU)-associated heat stress, highlighted the potential role of CLU-associated stress in promoting immune escape, and established a four-gene signature ( CLU, PDGFB, TIGIT, C3 ) indicating poor prognosis of GAS induced by CLU-associated stress and immune escape. Based on GAS-derived tumoroids retaining the histological features, CLU-associated stress, and genetic profile of parental tumor, we validated the anti-tumor and sensitizing DDP efficacy of targeting CLU.

Conclusion CLU-associated heat stress of key cell subtypes contributed to the malignant GAS microenvironment. Additionally, we pioneeringly constructed GAS-derived tumoroids and suggested that combining CLU-targeted treatment and DDP could improve the therapeutic efficacy for GAS.

Keywords

cervical gastric-type adenocarcinoma / precise treatment / tumoroid model / scRNA-seq / TCR-seq

Ethics statement

The current study was approved by the Ethics Committee of Ob-stetrics and Gynaecology Hospital of Fudan University (No. 2022- 105), and complied with the declaration of Helsinki. Informed con-sent was obtained from all participants.

Acknowledgements

This project was supported by funding from Medical Innovation Research of Shanghai Science and Technology (grant No. 22Y31900500 to K.H. and grant No.21Y11906900 to J.Q.), National Natural Science Foundation of China (grant No. 82173188 to K.H. and grant No. 82472993 to J.Q.), Shanghai Municipal Hospital Development Center (grant No. SHDC22021307 to K.H.), and Shanghai Municipal Health Commission (grant No. 202040498 to J.Q.).

Author contributions

Tong Wu (Conceptualization, Data curation, Visualization, Writing—original draft), Xinyu Qu (Visualization, Writing—review & editing), Lili Jiang (Conceptualization, Methodology), Tingting Ren (Validation), Qinqin Liu (Resources, Software), Xingyu Chang (Resources, Supervision), Meng Xie (Resources, Writing—review & editing), Keqin Hua (Funding acquisition, Writing—review & editing), and Junjun Qiu (Funding acquisition, Writing— review & editing).

Supplementary material

Supplementary material is available at PCMEDI Journal online.

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