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Transmissible ER stress reconfigures the AML bone marrow compartment.

ABSTRACT: Successive adaptation of the bone marrow (BM) from homeostatic hematopoietic microenvironment to a self-reinforcing niche is an integral aspect of leukemogenesis. Yet, the cellular mechanisms underlying these functional alterations remain to be defined. Here, we found that AML incursion precipitates compartmental endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in both leukemia and stromal cells. We observed that extracellular vesicles (EV) transmit ER stress in vivo from the AML xenograft to BM stroma, whereby the upregulation of core UPR components drives subsequent osteolineage differentiation of mesenchymal stem cells (MSC). Finally, we show that the underlying mechanism involves quantitative incorporation and cell-cell transfer of Bone Morphogenic Protein 2 (BMP2), a potent osteogenic signal, by AML-EVs. Corroborative studies in AML patient samples support the translational relevance of AML-EVs as a platform for BMP trafficking and source of compartmental crosstalk. Transmissible ER stress was previously identified as a source of chemoresistance in solid tumor models, and this work reveals a role in remodeling the BM niche in AML.

SUBMITTER: Doron B

PROVIDER: S-EPMC6411460 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Transmissible ER stress reconfigures the AML bone marrow compartment.

Doron Ben B Abdelhamed Sherif S Butler John T JT Hashmi Saman K SK Horton Terzah M TM Kurre Peter P

Leukemia 20180911 4

Successive adaptation of the bone marrow (BM) from homeostatic hematopoietic microenvironment to a self-reinforcing niche is an integral aspect of leukemogenesis. Yet, the cellular mechanisms underlying these functional alterations remain to be defined. Here, we found that AML incursion precipitates compartmental endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in both leukemia and stromal cells. We observed that extracellular vesicles (EV) transmit ER stress in vivo from ...[more]

PMID: 30206307

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Project description:Purpose: To investigate the critical role ER stress exhibit in cellular crosstalk between tumor cells and macrophages in the tumor microenvironment. We performed the two different polarized macrophages under ER stress and harvested the ER-stressed conditioned media. To figure out how two macrophage polarities generated conditioned media impact LLC tumor cells diversely, we use RNA-sequencing (RNA-seq) strategies to profile the deep-sequencing research and find the potential molecular mechanisms during the ER stress transmission from macrophages to tumor cells. The major differential influences the two macrophages proceeded were attribute to macrophages polarization characteristics, which instruct us to study the two polarized macrophages. Hence, we also performed RNA-sequencing during in vitro stimulation of ER stress inducer Tm in two polarized bone marrow derived macrophages. Methods: After different treatment, LLC tumor cells mRNA was extracted and LLC tumor cells transcriptome profiles were generated by deep sequencing, using Illumina. Under ER stress, the different polarized macrophages transcriptome profiles were also generated by deep sequencing, using Illumina. Results: Macrophages displayed different polarization characteristics could respond to ER stress differentially. Notably, GM-BMDMs were more susceptible to ER stress and facilitated the induction of proinflammatory signals, and M-BMDMs facilitate tumor growth, process, and metastasis. LLC cells exhibit different gene expression profiles in response to transferred ER stress from two polarized macrophage populations. Tumor cells that received transmissible ER stress from M2 macrophages has potential to facilitate the tumor survival, while transmissible ER stress from M1 macrophages could lead to more acute cell death and inflammation. Conclusion: Our study revealed that tumor cells could receive the transmissible ER stress from distinct macrophage populations with different extents of ER stress activation in the tumor microenvironment. The proinflammatory M1-like macrophages respond to ER stress more potently and transmit stronger ER stress to tumor cells. By analyzing the secreted components of two ER stressed macrophage populations, we identified that S100A8 and S100A9, which are dominantly secreted by M1-like macrophages, could lead to significant recipient tumor cell death in synergy with transferred ER stress.

Dataset Information

Transmissible ER stress reconfigures the AML bone marrow compartment.

Publications

Transmissible ER stress reconfigures the AML bone marrow compartment.

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