Geyer Marlene, Schreyer Daniel, Gaul Lisa-Marie, Pfeffer Susanne, Pilarsky Christian, Queiroz Karla
MIMETAS BV, De Limes 7, 2342DH, Oegstgeest, The Netherlands.
School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, G61 1BD, Glasgow, United Kingdom.
Cell Death Discov. 2023 Jan 21;9(1):20. doi: 10.1038/s41420-023-01334-z.
Pancreatic Ductal Adenocarcinoma (PDAC) is estimated to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. Standard of care chemotherapeutic treatment only prolongs the survival of patients for a short timeframe. Therefore, it is important to understand events driving treatment failure in PDAC as well as identify potential more effective treatment opportunities. PDAC is characterized by a high-density stroma, high interstitial pressure and very low oxygen tension. The aim of this study was to establish a PDAC platform that supported the understanding of treatment response of PDAC organoids in mono-, and co-culture with pancreatic stellate cells (PSCs) under hypoxic and normoxic conditions. Cultures were exposed to Gemcitabine in combination with molecules targeting relevant molecular programs that could explain treatment specific responses under different oxygen pressure conditions. Two groups of treatment responses were identified, showing either a better effect in monoculture or co-culture. Moreover, treatment response also differed between normoxia and hypoxia. Modulation of response to Gemcitabine was also observed in presence of a Hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor and HIF inhibitors. Altogether this highlights the importance of adjusting experimental conditions to include relevant oxygen levels in drug response studies in PDAC.
据估计，到2030年，胰腺导管腺癌（PDAC）将成为癌症相关死亡的第二大主要原因，死亡率高达93%。标准的护理化疗治疗只能在短时间内延长患者的生存期。因此，了解导致PDAC治疗失败的因素以及确定潜在的更有效的治疗机会非常重要。PDAC的特征是高密度基质、高间质压力和极低的氧张力。本研究的目的是建立一个PDAC平台，以支持在缺氧和常氧条件下，理解PDAC类器官在与胰腺星状细胞（PSC）进行单培养和共培养时的治疗反应。将培养物暴露于吉西他滨，并联合靶向相关分子程序的分子，这些分子程序可以解释在不同氧压条件下的治疗特异性反应。确定了两组治疗反应，分别显示出在单培养或共培养中有更好的效果。此外，常氧和缺氧条件下的治疗反应也有所不同。在缺氧诱导因子（HIF）脯氨酰羟化酶（PHD）抑制剂和HIF抑制剂存在的情况下，也观察到了对吉西他滨反应的调节。总之，这突出了在PDAC药物反应研究中调整实验条件以纳入相关氧水平的重要性。
