Navarro-Serer Bernat, Wissler Maria F, Glover Brandi K, Lerner Michael G, Oza Harsh H, Wang Vania, Knutsdottir Hidur, Shojaeian Fatemeh, Noller Kathleen, Baskaran Saravana Gowtham, Hughes Sarah, Weaver Alana M, Wilentz Daniel, Olayemi Oluwatobiloba, Bader Joel S, Fertig Elana J, Gilkes Daniele M, Wood Laura D
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Department of Physics, Engineering and Astronomy, Earlham College, Richmond, Indiana.
Cancer Res Commun. 2025 May 1;5(5):881-895. doi: 10.1158/2767-9764.CRC-24-0025.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal prognosis. PDAC develops in a hypoxic environment in which cells adapt and activate processes to allow survival under low-oxygen conditions, some of which may enhance the ability of cancer cells to invade locally or metastasize distantly. Using human PDAC organoids, we determined that hypoxia consistently enhanced invasion across 11 patient-derived models. Using RNA sequencing of hypoxic invasive organoids (compared with matched invasive normoxic organoids from the same patients), we identified prolyl 4-hydroxylase subunit alpha 1 (P4HA1) as a potential regulator of PDAC invasion in hypoxia. Leveraging publicly available datasets from human tissue, we determined that P4HA1 is more highly expressed in PDAC compared with normal pancreatic tissue and that high P4HA1 expression correlates with poor patient prognosis. To further interrogate the role of P4HA1 in invasion of hypoxic patient-derived organoids, we quantified invasion in organoids modified to knockdown or overexpress P4HA1, demonstrating that P4HA1 is necessary for hypoxia-enhanced invasion and sufficient to increase invasion in normoxia in PDAC organoids. Our results identify P4HA1 as a driver of PDAC organoid invasion in hypoxia.
This study demonstrates that hypoxia increases invasion across a cohort of human pancreatic cancer organoids and identifies the collagen-modifying enzyme P4HA1 as a driver of hypoxia-enhanced invasion. These results characterize a molecular mechanism by which the microenvironment alters tumor cell behavior and underscore new strategies to inhibit invasion.
胰腺导管腺癌（PDAC）是一种侵袭性很强的恶性肿瘤，预后很差。PDAC在缺氧环境中发展，细胞在这种环境下适应并激活一些过程以在低氧条件下存活，其中一些过程可能会增强癌细胞局部侵袭或远处转移的能力。利用人源PDAC类器官，我们确定缺氧在11个患者来源的模型中持续增强侵袭能力。通过对缺氧侵袭性类器官进行RNA测序（与来自同一患者的匹配的常氧侵袭性类器官相比），我们确定脯氨酰4-羟化酶亚基α1（P4HA1）是缺氧条件下PDAC侵袭的潜在调节因子。利用来自人体组织的公开数据集，我们确定与正常胰腺组织相比，P4HA1在PDAC中表达更高，且P4HA1高表达与患者预后不良相关。为了进一步探究P4HA1在缺氧患者来源类器官侵袭中的作用，我们对经过改造以敲低或过表达P4HA1的类器官中的侵袭进行了量化，证明P4HA1是缺氧增强侵袭所必需的，并且足以增加PDAC类器官在常氧条件下的侵袭。我们的结果确定P4HA1是缺氧条件下PDAC类器官侵袭的驱动因素。
本研究表明缺氧会增加一群人源胰腺癌类器官的侵袭能力，并确定胶原修饰酶P4HA1是缺氧增强侵袭的驱动因素。这些结果描述了一种微环境改变肿瘤细胞行为的分子机制，并强调了抑制侵袭的新策略。
