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

Abstract

Summary Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth3,4. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important tumor suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. PTEN level in PTEN-loss brain metastatic tumor cells is restored after leaving brain microenvironment. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting miRNAs to metastatic tumor cells, while astrocyte-specific depletion of PTEN-targeting miRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. 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 demonstrate a remarkable plasticity of PTEN expression in metastatic tumor 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 tumor cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for those brain metastasis patients who are in dire need.

PKB/Akt-dependent regulation of inflammation in cancer

“…Given a positive input from PKB towards IKK activation, it is tempting to speculate that PKB activation may positively regulate CCL2 expression. Indeed, expression of CCL2 is tightly controlled by NF-κB signaling partially through PKB activation in a PTEN-loss brain tumor model [105]. Furthermore, in an EMT induced immunosuppressive condition, CCL2 expression is regulated by the transcription factor Snail [106], which itself is negatively regulated by GSK3β, a direct target of PKB.…”

Extracellular RNA profiles with human age

“…miRNAs are resistant to nucleases due to their small size and the fact that in body fluids, they are likely protected in extracellular evesicles (EVs) or bound to protein or high‐density lipoprotein (HDL) binding partners (Brase, Wuttig, Kuner & Sultmann, 2010; Cortez et al., 2012; Reid, Kirschner & van Zandwijk, 2011; Wagner et al., 2013). This reservoir of miRNAs may transit to other cells and tissues where in some cases they influence gene regulation and may play a role in physiology and pathology (Hergenreider et al., 2012; Wei et al., 2017; Zhang et al., 2010, 2015). Earlier, we found that several circulating miRNAs are lower in abundance as humans age (Noren Hooten et al., 2010, 2013).…”

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

“…Multiple studies indicate that exosomes are actually involved in different phases of carcinogenesis and tumor development. [48][49][50][51][52][53][54][55] From the perspective of tumor-initiating property, Melo et al 17 demonstrated that the non-tumorigenic MCF10A cells formed tumor mass in nude mice when co-injected with cancer cell-derived exosomes, and Dicer blocking in these exosomes could reduce tumor formation. This oncogenic conversion of MCF10A cells attributes to precursor microRNAs (pre-miRNAs), along with Dicer, AGO2 (Argonaute2), and TRBP (HIV-1 TAR RNA binding protein) in exosomes of cancer cells.…”

“…In the respect of tumor metastasis, Zhou et al 51 showed that breast cancer-derived exosomes destroyed vascular endothelial barrier to facilitate metastasis by targeting the tight junction protein ZO-1 via exosomal miR-105. Zhang et al 52 revealed the role of exosomal cargo in tumor metastasis by conducting the following PTEN experiment. PTEN loss could promote the tumor-cell dissemination in the brain since PTEN is an important tumor suppressor.…”