PO.TB10.16 · 肿瘤生物学
钙稳态调节因子GRIN2D激活癌症相关成纤维细胞导致促纤维增生并促进胰腺导管腺癌中中性粒细胞浸润以形成中性粒细胞胞外诱捕网
Calcium homeostasis modulator GRIN2D activates cancer‐associated fibroblast for desmoplasia and promotes neutrophil infiltration for neutrophil extracellular trap formation in pancreatic ductal adenocarcinoma
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摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）因对免疫治疗应答不佳而被视为一种"冷肿瘤"，这在很大程度上归因于其致密而复杂的肿瘤微环境。钙离子（Ca 2+）是多种生物学过程的重要信号分子。钙通道和转运体失调极大地导致钙稳态异常，进而促进癌症进展。然而，其在PDAC肿瘤微环境和治疗耐药中的作用仍在很大程度上未知。我们此前证明了钙转运体谷氨酸离子型受体NMDA型2D亚基（GRIN2D）在促进PDAC肿瘤生长和肝转移中的重要性。本研究中，我们探讨了GRIN2D在肿瘤微环境和治疗耐药中的重要性。上调的GRIN2D激活癌症相关成纤维细胞（CAF）并促进中性粒细胞浸润，导致一个致癌性的肿瘤微环境。机制上，PDAC细胞中GRIN2D敲低后的转录组分析将纤连蛋白1（FN1）和白细胞介素-1 beta（IL-1beta）鉴定为钙信号下GRIN2D的下游靶点。GRIN2D-FN1通路激活CAF以促进肿瘤促纤维增生，而GRIN2D-IL-1beta通路促进中性粒细胞浸润和中性粒细胞胞外诱捕网形成。此外，我们揭示了导致PDAC中GRIN2D上调的表观遗传机制。我们在GRIN2D处鉴定出一个高甲基化的外显子-CpG岛，促进PDAC肿瘤中GRIN2D的表达。靶向肿瘤微环境中的GRIN2D可增强化疗和免疫治疗抑制肿瘤生长和转移的疗效。本项目所获得的知识揭示了GRIN2D和钙稳态在PDAC进展中的重要性，并为PDAC提供了新的治疗靶点。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) is recognized as a “cold tumor” due to its poor response to immunotherapy, which is greatly contributed by the dense and complicated tumor microenvironment. Calcium ions (Ca 2+ ) are important signaling molecules for various biological processes. Dysregulated calcium channels and transporters greatly contribute to abnormal calcium homeostasis and, in turn, promote cancer progression. However, its roles in the PDAC tumor microenvironment and therapeutic resistance are still largely unknown. We previously demonstrated the importance of calcium transporters glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D) in promoting PDAC tumor growth and liver metastasis. Here, we studied the importance of GRIN2D in the tumor microenvironment and therapeutic resistance. The upregulated GRIN2D activated cancer-associated fibroblast (CAF) and promoted neutrophil infiltration, contributing to an oncogenic tumor microenvironment. Mechanistically, transcriptome profiling after GRIN2D knockdown in PDAC cells identified fibronectin 1 (FN1) and interleukin-1 beta (IL-1beta) as GRIN2D downstream targets under calcium signaling. The GRIN2D-FN1 pathway activated CAF for tumor desmoplasia, while the GRIN2D-IL-1beta pathway promoted neutrophil infiltration and neutrophil extracellular traps formation. Furthermore, we revealed the epigenetic mechanism leading to the upregulation of GRIN2D in PDAC. We identified a hypermethylated Exon-CpG island at GRIN2D, promoting GRIN2D expression in PDAC tumors. Targeting GRIN2D in the tumor microenvironment enhances the efficacy of both chemotherapies and immunotherapies in inhibiting tumor growth and metastasis. Knowledge gained from this project uncovers the importance of GRIN2D and calcium homeostasis in PDAC progression and contributes to novel therapeutic targets in PDAC.
利益披露 Disclosure
C. Wong, None..
Y. Kwan, None..
K. To, None..
Y. Chen, None.