Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth

By Lin Zhang, Siyuan Zhang, Jun Yao, Frank J. Lowery, Qingling Zhang, Wen-Chien Huang, Ping Li, Min Li, Xiao Wang, Chenyu Zhang and 12 more. Nature, 2015

1,091 citations recorded by the source corpus.

The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells’ adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0bfcdbcf743e3dea0a6e7768a5624b10a3940d9e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. J. Joyce
2. Raghu Kalluri
3. Sybren L. N. Maas
4. Yan Luo
5. Ben Wang
6. Alissa M. Weaver
7. D. Quail
8. Chuanjiang He

In Molecular Biology

1. J. Joyce
2. Raghu Kalluri
3. D. Lyden
4. Sybren L. N. Maas
5. Akiko Takahashi
6. H. Peinado
7. Yan Luo
8. Ben Wang

Citations in the corpus

• Effect of exosomal miRNA on cancer biology and clinical applications (2018, background): “For example, after metastasis to the brain, but not to other organs, human and mouse tumor cells regulated by microRNAs from brain astrocytes both lost PTEN expression [50].”
• The biology, function, and biomedical applications of exosomes (2020, neutral): “Another example of stromal exosomal cargo promoting cancer cell progression includes astrocytederived miR-19a delivered to breast cancer cells, which results in PTEN (phosphatase and tensin homolog) suppression and contributed tometastasis (160).”
• Extracellular vesicles in cancer: cell-to-cell mediators of metastasis (2016, background): “…of miRNAs specifically targeting PTEN expression from astrocyte-derived exosomes to invading tumor cells in the brain microenvironment promotes establishment of brain metastasis, although other autocrine and paracrine signaling may also cooperate during tumor progression (Zhang et al., 2015).”
• Systems Biology of Cancer Metastasis (2019, background): “Astrocyte-derived exosomes suppress PTEN in dormant metastatic cells, allowing for the outgrowth of lesions in the brain(Zhang et al., 2015), thus demonstrating a role for the microenvironment in guiding the reactivation of dormant cancer cells.”
• Exosomes maintain cellular homeostasis by excreting harmful DNA from cells (2017, positive): “We thus tried to inhibit exosome secretion by knocking down Alix or Rab27a, which are essential components of exosome biogenesis 34 and secretion 35 , respectively, using previously validated small interfering RNAs (siRNAs) 36,37 in senescent cells.”
• Extracellular Vesicles: Unique Intercellular Delivery Vehicles. (2017, background): “Consistent with the tumor supportive role of these infiltrating cells, co-cultures of metastatic breast cancer cells and a microglial cell-line enhanced proliferation and inhibited apoptosis of the tumor cells [128].”
• Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer (2017, neutral): “E vesicles (EVs) are mediators of juxtacrine and paracrine signaling required for metastatic progression (1, 2).”
• Exosome Theranostics: Biology and Translational Medicine (2018, background): “Furthermore, this adaptive PTEN loss was found to increase secretion of the cytokine chemokine (C-C motif) ligand 2 (CCL2) and recruits Iba1-expressing myeloid cells, further reciprocally enhancing the proliferation and reducing the apoptosis of tumor cells, thereby triggering the outgrowth of brain”