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Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment

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Abstract

Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR) and is decisive for tumor cell growth and tumor microenvironment (TME) maintenance. Tumor cells persistently undergo ER stress and could transmit it to the neighboring macrophages and surroundings. Tumor infiltrating macrophages can also adapt to the microenvironment variations to fulfill their highly energy-demanding and biological functions via ER stress. However, whether the different macrophage populations differentially sense ER stress and transmit ER stress to surrounding tumor cells has not yet been elucidated. Here, we aimed to investigate the role of transmissible ER stress, a novel regulator of intercellular communication in the TME. Murine bone marrow-derived macrophage (BMDM) can be polarized toward distinct functional endpoints termed classical (M1) and alternative (M2) activation, and their polarization status has been shown to be tightly correlated with their functional significance. We showed that tumor cells could receive the transmissible ER stress from two differentially polarized macrophage populations with different extent of ER stress activation. The proinflammatory M1-like macrophages respond to ER stress with less extent, however they could transmit more ER stress to tumor cells. Moreover, by analyzing the secreted components of two ER-stressed macrophage populations, we identified certain damage-associated molecular patterns (DAMPs), including S100A8 and S100A9, which are dominantly secreted by M1-like macrophages could lead to significant recipient tumor cells death in synergy with transferred ER stress.

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Data availability

The data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE193669. (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193669).

Abbreviations

ER:

Endoplasmic reticulum

TME:

Tumor microenvironment

UPR:

Unfolded protein response

DC:

Dendritic cell

TLR:

Toll-like receptor

M-CSF:

Macrophage colony-stimulating factor

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

TAM:

Tumor-associated macrophage

GM-BMDM:

GM-CSF cultured bone marrow-derived macrophage

M-BMDM:

M-CSF cultured bone marrow-derived macrophage

DAMP:

Damage-associated molecular pattern

MAPK:

Mitogen-activated protein kinase

Tm:

Tunicamycin

Tg:

Thapsigargin

CM:

Conditioned media

Grp78:

Glucose-regulated protein-78

sXbp1:

Spliced X-box binding protein 1

CHOP:

C/EBP homologous protein

IL:

Interleukin

CXCL1:

C–X–C motif chemokine ligand 1

cPARP:

Cleaved Poly (adp-ribose) polymerase

p-JNK:

Phosphorylated c-Jun N-terminal kinase

p-ERK:

Phosphorylated extracellular signal-regulated kinase

NT:

No treatment

DEG:

Differentially expressed gene

GO:

The Gene Ontology

IFN:

Interferon

IPA:

Ingenuity pathway analysis

EV:

Extracellular vesicle

TNF:

Tumor necrosis factor

ICD:

Immunogenic cell death

DMEM:

Dulbecco's modified eagle medium

RT-PCR:

Reverse transcription polymerase chain reaction

FC:

Fold change

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Acknowledgements

This work was supported by the Major Program of National Natural Science Foundation of China (81991525) and Key R&D Program of Shandong Province (2020CXGC010503).

Funding

This work was supported by the Major Program of National Natural Science Foundation of China (81991525) and Key R&D Program of Shandong Province (2020CXGC010503).

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Authors and Affiliations

  1. Institute of Cancer Biology and Drug Screening, School of Life Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China

    Wei Wei & Jinbo Yang

  2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Chinese Ministry of Education, Qingdao, 266100, Shandong, China

    Wei Wei, Yazhuo Zhang, Qiaoling Song, Qianyue Zhang, Xiaonan Zhang, Xinning Liu, Zhihua Wu, Xiaohan Xu, Yuting Xu, Yu Yan, Chenyang Zhao & Jinbo Yang

  3. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, Shandong, China

    Yazhuo Zhang, Qiaoling Song, Qianyue Zhang, Xinning Liu, Xiaohan Xu, Yuting Xu, Yu Yan, Chenyang Zhao & Jinbo Yang

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  1. Wei Wei
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  2. Yazhuo Zhang
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  3. Qiaoling Song
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  9. Yuting Xu
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  10. Yu Yan
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  11. Chenyang Zhao
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Contributions

All authors participated in designing the study as well as interpreting the whole data. CZ and JY supervised the study; WW, YZ, XZ, ZW, XX and YY performed and evaluated individual experiments; YX and QZ performed bioinformatical analyses; WW, XL, QS, CZ and JY wrote the manuscript with the contributions from all the authors.

Corresponding authors

Correspondence to Chenyang Zhao or Jinbo Yang.

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The authors have declared no conflicts of interests.

Ethical approval

The study was approved by the Committee on the Ethics of Animal Experiments of the School of Life Sciences of Lanzhou University (EAF-2021026).

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Wei, W., Zhang, Y., Song, Q. et al. Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment. Cell. Mol. Life Sci. 79, 403 (2022). https://doi.org/10.1007/s00018-022-04413-z

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