Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels.
Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels.
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DOI：
10.1038/s41467-018-07339-y
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发表时间：
2018-11-29
影响因子：
16.6
通讯作者：
Norman JC
中科院分区：
文献类型：
--
作者：
Novo D;Heath N;Mitchell L;Caligiuri G;MacFarlane A;Reijmer D;Charlton L;Knight J;Calka M;McGhee E;Dornier E;Sumpton D;Mason S;Echard A;Klinkert K;Secklehner J;Kruiswijk F;Vousden K;Macpherson IR;Blyth K;Bailey P;Yin H;Carlin LM;Morton J;Zanivan S;Norman JC
突变体p53 （mutp53）通过上调rab偶联蛋白（RCP）和二酰基甘油激酶-α (DGKα)依赖的内体循环来增加癌症侵袭性。在这里，我们报道了表达mutp53的肿瘤细胞产生外泌体，通过增加其他肿瘤细胞中rcp依赖的整合素循环，介导mutp53侵袭/迁移功能获得的细胞间转移。这一过程依赖于mutp53控制唾液黏液蛋白、足霉霉素产生的能力，以及Rab35 GTPase的活性，后者与足霉霉素相互作用，影响其对外泌体的分类。来自表达mutp53的肿瘤细胞的外泌体也会影响正常成纤维细胞中的整合素运输，从而促进高度亲侵入性的细胞外基质（ECM）的沉积，定量二次谐波生成显微镜显示这种ECM表现出典型的正交形态。携带mutp53驱动的胰腺腺癌小鼠的肺ECM也显示出在转移之前增加的正交特征，这表明mutp53可以通过一种支持侵袭性生长的方式影响远端器官的微环境。一些p53突变体在体内促进癌细胞的侵袭性迁移和肿瘤的转移。然而，这些现象背后的关键机制细节仍不清楚。在这里，作者提出了一种涉及成纤维细胞的非细胞自主机制，即表达p53的突变癌细胞激活外泌体介导的机制，影响成纤维细胞中的整合素循环，从而影响细胞外基质重塑，有利于癌细胞的侵袭和迁移。
Mutant p53s (mutp53) increase cancer invasiveness by upregulating Rab-coupling protein (RCP) and diacylglycerol kinase-α (DGKα)-dependent endosomal recycling. Here we report that mutp53-expressing tumour cells produce exosomes that mediate intercellular transfer of mutp53’s invasive/migratory gain-of-function by increasing RCP-dependent integrin recycling in other tumour cells. This process depends on mutp53’s ability to control production of the sialomucin, podocalyxin, and activity of the Rab35 GTPase which interacts with podocalyxin to influence its sorting to exosomes. Exosomes from mutp53-expressing tumour cells also influence integrin trafficking in normal fibroblasts to promote deposition of a highly pro-invasive extracellular matrix (ECM), and quantitative second harmonic generation microscopy indicates that this ECM displays a characteristic orthogonal morphology. The lung ECM of mice possessing mutp53-driven pancreatic adenocarcinomas also displays increased orthogonal characteristics which precedes metastasis, indicating that mutp53 can influence the microenvironment in distant organs in a way that can support invasive growth. Some p53 mutants promote invasive migration of cancer cells and metastasis of tumours in vivo. However the key mechanistic details behind these phenomena remain unclear. Here the authors propose a non-cell autonomous mechanism involving fibroblasts, whereby mutant p53-expressing cancer cells activate an exosome-mediated mechanism that influences integrin recycling in fibroblasts, thus influencing extracellular matrix remodelling to favour cancer cell invasion and migration.
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影响因子：
16.6
作者：
Gundry C;Marco S;Rainero E;Miller B;Dornier E;Mitchell L;Caswell PT;Campbell AD;Hogeweg A;Sansom OJ;Morton JP;Norman JC
通讯作者：
Norman JC
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
DOI：
10.1083/jcb.201109112
发表时间：
2012-01-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rainero E;Caswell PT;Muller PA;Grindlay J;McCaffrey MW;Zhang Q;Wakelam MJ;Vousden KH;Graziani A;Norman JC
通讯作者：
Norman JC
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
64.8
作者：
Bailey, Peter;Chang, David K.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.