Metastasis is the number one cause of cancer-related mortality. Major neoplastic diseases such as melanoma, lung, breast, and colon cancers have high incidences of brain metastases. One-year survival after diagnosis of brain metastasis is less than 20%. Cancer cells dynamically interacts with specific organ microenvironments to establish metastasis as depicted by the “seed and soil” hypothesis. Yet it is unclear when and how disseminated tumor cells acquire the essential traits from the brain microenvironment that primes their subsequent metastatic outgrowth.
Here we found that primary tumor cells with normal PTEN expression lose PTEN after dissemination to the brain, but not to other organs. Metastatic brain tumor cells that have experienced PTEN loss have PTEN levels restored once they leave the brain. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocyte-derived exosomes. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis.
Our findings signify the dynamic and reciprocal cross-talk between tumor cells and other brain stromal cells. Disseminated tumor cells acquire the essential traits from the microenvironment of brain that prime their outgrowth. Importantly, our finding provides new opportunities for effective anti-metastasis therapies: inhibiting CCL2 might be an effective therapeutic intervention of life-threatening brain metastases.
Citation Format: Lin Zhang, Siyaun Zhang, Jun Yao, Frank J. Lowery Lowery, Qingling Zhang, Wen-Chien Huang, Ping Li, Min Li, Xiao Wang, Chenyu Zhang, Hai Wang, Kenneth Ellis, Mujeeburahiman Cheerathodi, Joseph McCarty, Diane Palmieri, Patricia Steeg, Jodi S Saunus, Sunil Lakhani, Suyun Huang, Aysegul Sahin, Kenneth Aldape, Dihua Yu. Brain microenvironment induced PTEN loss by microRNAs promotes brain metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 907.