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 a team led by researchers at M. D. Anderson Cancer Center shows 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.
a, Intercellular transfer of miR-19a. Top, light microscopy and fluorescent images of HCC1954 cells 12 and 60 h after co-culture with astrocytes loaded with Cy3-labelled miR-19a. Bottom, flow cytometry analysis of Cy3-miR-19a in tumour cells 60 h after co-culture (mean ± s.e.m., t-test, P < 0.05, 3 biological replicates). b, c, Transmission electron microscopy of exosome vesicles in astrocyte-conditioned media (b), confirmed by western blot for CD63, CD81 and TSG101 exosome markers released by 1 × 106 CAFs or astrocytes (c). d, Representative data showing presence of Cy3-miR-19a in HCC1954 breast cancer cells after adding exosomes purified from Cy3-miR-19a-transfected astrocytes for 24 h. Bottom, flow cytometry analysis of Cy3-miR-19a-positive HCC1954 cells after treatment with supernatant (without exosomes), or exosomes purified from Cy3-miR-19a-transfected astrocytes. Negative control is HCC1954 cells without treatment. Positive control is Cy3-miR-19a-transfected astrocytes (3 biological replicates).
These 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. These 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.