【Nature】脑微环境通过外泌体（exosome）microRNAs促进肿瘤转移 - 外泌体之家 | 细胞外膜泡领域核心平台—exosomes & microvesicles—小膜泡大作用

威胁生命的癌症在远处器官转移需要被传播的肿瘤细胞与截然不同的微环境的转移位点相适应和共同进化。相同来源的肿瘤细胞转移到不同的器官后会显示出不同的基因表达谱。显然，转移的肿瘤细胞和外在信号之间在转移器官的动态相互作用影响其转移后的生长。然而，扩散的肿瘤细胞在什么时候并且怎么样获得转移器官的利于转移肿瘤细胞生长微环境的仍然是不清楚的。这篇研究文章揭示了正常表达PTEN（一种重要的肿瘤抑制因子）的人和小鼠的肿瘤细胞在传播到脑部后丢失PTEN的表达，但是传播到其他器官后不会。在转移到脑后丢失PTEN的肿瘤细胞在离开脑部微环境后PTEN的表达水平会得到恢复。这种脑微环境依赖的、可逆的PTEN mRNA和蛋白下调是有脑部星型胶质细胞来源的microRNAs调控的。星型胶质细胞来源的exosome介导了与转移肿瘤细胞之间的靶向PTEN的microRNAs的传递。体内实验证明，星型胶质细胞特异性敲除靶向PTEN的microRNAs或者阻断星型胶质细胞分泌exosome可恢复PTEN并抑制脑部的转移。此外，这种适应性脑转移肿瘤细胞的PTEN丢失导致趋化因子CCL2分泌的增加，招募表达IBA1表达的骨髓来源的细胞，从而通过增加繁殖和抑制凋亡来相互促进脑转移肿瘤细胞的生长。该研究揭示了转移肿瘤细胞的PTEN表达对不同器官微环境的显著可塑性，为转移细胞与其微环境的在适应性转移生长的过程中相互影响的重要作用提供了重要的证据。该研究发现阐明了肿瘤细胞与转移微环境的动态、相互的交流的新机制，更重要的是，为抑制肿瘤转移，尤其是脑转移提供了新的策略。

Thedevelopment of life-threatening cancer metastases at distant organs requiresdisseminated tumour cells' adaptation to, and co-evolution with, thedrastically different microenvironments of metastatic sites. Cancer cells ofcommon origin manifest distinct gene expression patterns after metastasizing todifferent organs. Clearly, the dynamic interaction between metastatic tumourcells and extrinsic signals at individual metastatic organ sites criticallyeffects the subsequent metastatic outgrowth. Yet, it is unclear when and howdisseminated tumour cells acquire the essential traits from themicroenvironment of metastatic organs that prime their subsequent outgrowth.Here we show that both human and mouse tumour cells with normal expression ofPTEN, an important tumour suppressor, lose PTEN expression after disseminationto the brain, but not to other organs. The PTEN level in PTEN-loss brainmetastatic tumour cells is restored after leaving the brain microenvironment.This brain microenvironment-dependent, reversible PTEN messenger RNA andprotein downregulation is epigenetically regulated by microRNAs from brainastrocytes. Mechanistically, astrocyte-derived exosomes mediate anintercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, whileastrocyte-specific depletion of PTEN-targeting microRNAs or blockade ofastrocyte exosome secretion rescues the PTEN loss and suppresses brainmetastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatictumour cells leads to an increased secretion of the chemokine CCL2, whichrecruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowthof brain metastatic tumour cells via enhanced proliferation and reducedapoptosis. Our findings demonstrate a remarkable plasticity of PTEN expressionin metastatic tumour cells in response to different organ microenvironments,underpinning an essential role of co-evolution between the metastatic cells andtheir microenvironment during the adaptive metastatic outgrowth. Our findings signifythe dynamic and reciprocal cross-talk between tumour cells and the metastaticniche; importantly, they provide new opportunities for effectiveanti-metastasis therapies, especially of consequence for brain metastasispatients.

外泌体之家 | 细胞外膜泡领域核心平台—exosomes &amp; microvesicles—小膜泡大作用

外泌体之家 | 细胞外膜泡领域核心平台—exosomes & microvesicles—小膜泡大作用