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 ...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-associatedγδT 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,and 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.展开更多
基金supported by funding from Medical Innova-tion 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.)+1 种基金Shanghai Municipal Hospital De-velopment Center(grant No.SHDC22021307 to K.H.)Shang-hai Municipal Health Commission(grant No.202040498 to J.Q.)。
文摘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-associatedγδT 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,and 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.
