小柯机器人

美国波士顿儿童医院Nada Y. Kalaany研究团队发现，鸟氨酸氨基转移酶支持胰腺癌中的多胺合成。这一研究成果于2023年3月29日在线发表在国际学术期刊《自然》上。

研究人员在人类和小鼠的体外和体内模型中使用遗传和药理学方法，表明胰腺导管腺癌（PDA）对来自谷氨酰胺的从头鸟氨酸合成有明显的依赖性。研究人员发现，这一过程是通过鸟氨酸氨基转移酶（OAT）介导的，它支持多胺的合成，并且是肿瘤生长所需的。这种定向的OAT活动通常主要限于婴儿期，与大多数成人正常组织和其他癌症类型依赖精氨酸衍生的鸟氨酸进行多胺合成形成鲜明对比。这种依赖性与PDA肿瘤微环境中的精氨酸耗竭有关，并且是由突变的KRAS驱动。

激活的KRAS诱导OAT和多胺合成酶的表达，导致PDA肿瘤细胞的转录组和开放染色质结构的改变。PDA（而不是正常组织）对OAT介导的从头合成鸟氨酸的明显依赖，为治疗胰腺癌患者提供了一个有吸引力的治疗窗口，而且毒性最小。

据悉，PDA是一种高度致命的恶性肿瘤，发病率不断上升，预后不佳，因此需要开发有效的治疗方法。尽管十多年来，针对肿瘤代谢的治疗一直是研究的重点，但肿瘤代谢的可塑性和高风险的毒性限制了这种抗癌策略。

附：英文原文

Title: Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

Author: Lee, Min-Sik, Dennis, Courtney, Naqvi, Insia, Dailey, Lucas, Lorzadeh, Alireza, Ye, George, Zaytouni, Tamara, Adler, Ashley, Hitchcock, Daniel S., Lin, Lin, Hoffman, Megan T., Bhuiyan, Aladdin M., Barth, Jaimie L., Machacek, Miranda E., Mino-Kenudson, Mari, Dougan, Stephanie K., Jadhav, Unmesh, Clish, Clary B., Kalaany, Nada Y.

Issue&Volume: 2023-03-29

Abstract: There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

DOI: 10.1038/s41586-023-05891-2

Source: https://www.nature.com/articles/s41586-023-05891-2

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