Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Master Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
Nat Commun. 2022 May 26;13(1):2945. doi: 10.1038/s41467-022-30638-4.
Tumor cells with diverse phenotypes and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia with fibroblasts as the major cell type. In the present study, we observe enrichment of myofibroblasts in a juxta-tumoral position with tumor cells undergoing epithelial-mesenchymal transition (EMT) that facilitates invasion and correlates with a worse clinical prognosis in PDAC patients. Direct cell-cell contacts forming heterocellular aggregates between fibroblasts and tumor cells are detected in primary pancreatic tumors and circulating tumor microemboli (CTM). Mechanistically, ATP1A1 overexpressed in tumor cells binds to and reorganizes ATP1A1 of fibroblasts that induces calcium oscillations, NF-κB activation, and activin A secretion. Silencing ATP1A1 expression or neutralizing activin A secretion suppress tumor invasion and colonization. Taken together, these results elucidate the direct interplay between tumor cells and bound fibroblasts in PDAC progression, thereby providing potential therapeutic opportunities for inhibiting metastasis by interfering with these cell-cell interactions.
具有不同表型和生物学行为的肿瘤细胞通过分泌因子或直接细胞-细胞接触受基质细胞影响。胰腺导管腺癌（PDAC）的特征是广泛的纤维母细胞性间质增生，其中纤维母细胞是主要的细胞类型。在本研究中，我们观察到肿瘤细胞发生上皮-间充质转化（EMT）时，肌成纤维细胞在肿瘤旁位置富集，这有利于侵袭，并与 PDAC 患者的更差临床预后相关。在原发性胰腺肿瘤和循环肿瘤微栓子（CTM）中检测到纤维母细胞和肿瘤细胞之间形成异细胞聚集的直接细胞-细胞接触。在机制上，肿瘤细胞中过度表达的 ATP1A1 与纤维母细胞的 ATP1A1 结合并重新排列，从而诱导钙震荡、NF-κB 激活和激活素 A 分泌。沉默 ATP1A1 表达或中和激活素 A 分泌可抑制肿瘤侵袭和定植。总之，这些结果阐明了 PDAC 进展中肿瘤细胞与结合的纤维母细胞之间的直接相互作用，从而为通过干扰这些细胞-细胞相互作用抑制转移提供了潜在的治疗机会。
