PO.MCB09.06 · 分子与细胞生物学
谷氨酰胺转运体ASCT2作为HPV阳性HNSCC类器官模型中的治疗靶点
Glutamine transporter ASCT2 as a therapeutic target in HPV positive organoid models of HNSCC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，人乳头瘤病毒（HPV）-16感染是其病因之一。既往研究表明，谷氨酰胺是为增殖细胞提供碳和氮的关键氨基酸。特别是，某些癌细胞通过代谢重编程增加谷氨酰胺的摄取。然而，我们对HNSCC中谷氨酰胺代谢和转运的理解仍然有限。在本研究中，我们将在患者来源的正常扁桃体类器官和HPV16阳性扁桃体类器官中研究谷氨酰胺转运，特别是ASCT2。
方法：扁桃体组织取自扁桃体切除术并加工用于类器官生成。通过机械和酶促解离，将扁桃体组织解离成单细胞悬液并接种于细胞外基质中。使用HPV16慢病毒感染扁桃体类器官，作为癌前HPV16阳性HNSCC模型。提取正常扁桃体和HPV+类器官的RNA用于qPCR分析。用V-9302（一种ASCT2竞争性拮抗剂）处理类器官以测定IC50。
结果：本研究在患者来源的正常扁桃体类器官和HPV16阳性扁桃体类器官中研究了谷氨酰胺转运体ASCT2。通过qPCR分析，两种类器官模型均表达ASCT2，其中HPV16阳性扁桃体类器官表达的ASCT2低于正常扁桃体类器官（FC 0.64，p<0.00）。为了解ASCT2是否可作为治疗靶点，用V-9302处理正常扁桃体类器官和HPV16阳性扁桃体类器官。获得了类器官的V-9302 IC50，其中HPV16阳性类器官（IC50：15.37 μM）比正常扁桃体类器官（IC50：20.50 μM）更敏感。
结论：谷氨酰胺是细胞生长和增殖的必需氨基酸，尤其是在快速生长的肿瘤中。由于V-9302对HPV16阳性类器官更敏感，V-9302显示出作为HNSCC治疗药物的潜力。未来研究将聚焦于V-9302对患者来源HNSCC肿瘤类器官的敏感性。
查看英文原文 English abstract
Background : Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with Human Papillomavirus (HPV) - 16 infections being a cause. Previous studies have shown that glutamine is a crucial amino acid that provides carbon and nitrogen for proliferating cells. In particular, some cancer cells increase the uptake of glutamine through metabolic reprogramming. However, our understanding of glutamine metabolism and transport remains limited in HNSCC. In this study, we will be investigating glutamine transport, specifically ASCT2, in patient-derived normal tonsil organoid and HPV16-positive tonsil organoids.
Methods : Tonsil tissue is obtained from tonsillectomy and process for organoid generation. Through mechanical and enzymatic dissociation, tonsil tissue is dissociated into single cell suspension and plated in extracellular matrices. HPV16 lentivirus is used to infect tonsil organoids and used as premalignant HPV16-positive HNSCC model. RNA of the normal tonsil and HPV+ organoids were extracted for qPCR analysis. V-9302, an ASCT2 competitive antagonist, was treated to the organoids for IC 50.
Results : In this study, the glutamine transporter, ASCT2, was investigated in patient-derived normal tonsil organoid and HPV16-positive tonsil organoids. Both organoid models exhibit ASCT2 through qPCR analysis, with HPV16-positive tonsil organoids exhibiting less ASCT2 (FC 0.64 p<0.00) than normal tonsil organoids. To see if ASCT2 can be a therapeutic target, V-9302 was treated to normal tonsil organoids and HPV16-positive tonsil organoids. V-9302 IC 50 of the organoids were obtained, with HPV16-positive organoids being more sensitive (IC 50 : 15.37 μM) than normal tonsil organoids (IC 50 : 20.50 μM).
Conclusion : Glutamine is an essential amino acid for cell growth and proliferation, especially in fast growing tumors. With V-9302 being more sensitive to HPV16-positive organoids, V-9302 shows the potential to be used as a therapeutic drug for HNSCC treatment. Future studies will focus on V-9302 sensitivity in patient-derived HNSCC tumor organoids.
利益披露 Disclosure
S. Cheng, None..
E. Jackert, None..
L. Tang, None..
D. Kwon, None..
N. Kokot, None..
U. Sinha, None..
Y. Chai, None..
A. Y. Han, None.