Application of organoid culture from HPV18‐positive small cell carcinoma of the uterine cervix for precision medicine

Abstract

Background Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)‐associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV‐associated cancer using patient‐derived organoid. Methods Organoid was established from the biopsy of a patient diagnosed with HPV18‐positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA‐seq analysis. Drug sensitivity testing was performed using organoids and organoid‐derived mouse xenograft model. Results WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA‐seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto‐oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti‐cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model. Conclusion In this study, we confirmed two strategies for identifying therapeutic targets of HPV‐derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV‐positive SCCC.

Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids

“…It is likely that specific culture conditions favour specific mutational loads and the importance of culture conditions on chemoresistance and marker gene expression has been pointed out recently [54]. So far, few other groups have described the establishment of cervical cancer organoids [23, 55, 56]. In our study, patient-derived organoids show clear deviations from immortalized cell lines.…”

“…Therefore, our individualised organoid systems, complemented with our newly developed automated readout tools to predict treatment responses, would present an important tool to foster personalised therapy in cervical cancer. In hindsight of our study and the results of others [54–56], the optimization of cervical cancer organoid establishment pipelines with the aim of personalized medicine and treatment options should focussed, especially if surgery is excluded as therapeutic option. The direct correlation of driver mutations, protein expression and activation to potential therapy options should be emphasized and pave the way to novel target driven therapies.…”

“…All of our isolates show resistant phenotypes that are affected by ADAM10/17 inhibition. Interestingly, while all our organoid isolates exhibited resistant phenotypes to cisplatin treatment, others found varying responses based on tumour origin and phenotype [55, 56].…”

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

“…Kusakabe et al. found that the fusion of HPV18 and chromosome 8q24.21 was capable of enhancing the expression level of the MYC gene ( 66 ), suggesting that it further promoted the development of tumors because of the role of MYC in accelerating tumor progression. But there was no study about its function in BC.…”

“…On the other hand, CNV analysis showed that the amplification of 3q26.32, 5p15.33 and 8q24.21, and the deletion of 5q21.3, 8p23.2 and 9p21.3 were primarily founded in high-risk patients. Kusakabe et al found that the fusion of HPV18 and chromosome 8q24.21 was capable of enhancing the expression level of the MYC gene (66), suggesting that it further promoted the development of tumors because of the role of MYC in accelerating tumor progression. But there was no study about its function in BC.…”