Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts.
Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts.
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上皮源性胰腺肿瘤周围的间质室被认为在这种恶性肿瘤的侵袭性表型中起关键作用。越来越多的证据表明，癌相关成纤维细胞（CAFs）是胰腺肿瘤基质中最丰富的细胞，有助于肿瘤的侵袭、转移和对治疗的抵抗，但调节CAFs行为的确切分子机制尚不清楚。在这项研究中，我们利用永生化的人胰腺CAFs来研究控制CAFs基质重塑和促进侵袭活性的分子途径。我们之前的研究表明，肌动蛋白相关蛋白palladin在胰腺肿瘤和其他实体肿瘤的cas中高水平表达，也在人类cas的永生化系中表达。在这项研究中，我们发现，短期暴露于酚酯的CAFs减少了应力纤维的数量，并引发了CAFs中单个侵入性和侵入性玫瑰花的出现。对内殖体的分子分析表明，它们的组成与其他细胞类型中描述的相似结构（即内殖体和足质体）相似。药理抑制和小干扰RNA敲低实验表明，蛋白激酶C、小GTPase Cdc42和钯素是CAFs有效组装入侵物所必需的。此外，GTPase活性测定表明，钯金有助于Cdc42的激活。在使用CAFs和肿瘤细胞混合的小鼠异种移植实验中，在CAFs中palladin的表达促进了人胰腺肿瘤细胞的快速生长和转移。总之，这些结果表明，高水平的palladin在CAFs中的表达通过调节Cdc42的活性来增强其重塑细胞外基质的能力，而Cdc42的活性反过来又促进了CAFs中基质降解侵入体的组装和肿瘤细胞的侵袭。总之，这些结果确定了一个新的分子信号通路，可能为抑制胰腺癌转移提供新的分子靶点。
The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor’s invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.
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