Evidence map›Paper›PMID 30799198›Full record

ArticleEBioMedicine2019

Oxidized ATM-mediated glycolysis enhancement in breast cancer-associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling.

Kexin Sun, Shifu Tang, Yixuan Hou, Lei Xi, Yanlin Chen, Jiali Yin, Meixi Peng, Maojia Zhao, Xiaojiang Cui, Manran Liu

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 84 papers.

0numbers the graph read from it
0cells of the map it votes in
84citing papers in PubMed
4.0field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

84 citing papers in PubMed, 127 citations in OpenAlex.

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24 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 2 countries.

Kexin SunKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Shifu TangKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China; Department of Laboratory Medicine, Liuzhou Traditional Chinese Medical Hospital, Liuzhou 545001, Guangxi, China; Department of Laboratory Medicine, The Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou 545001, Guangxi, China.
Yixuan HouKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China; Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing 400016, China.
Lei XiKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Yanlin ChenKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Jiali YinKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Meixi PengKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Maojia ZhaoKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Xiaojiang CuiDepartment of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 91006, USA.
Manran LiuKey Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China. Electronic address: manranliu@cqmu.edu.cn.
Chongqing Medical University · CNChildren's Hospital of Chongqing Medical University · CNCedars-Sinai Medical Center · US

Funding

The Role of FOXCI in Basal-like Breast CancerR01CA151610 · NCI · SAINT JOHN'S CANCER INSTITUTE · PI CUI, XIAOJIANG · 2011 to 2022
$3.8M
NCI NIH HHS R01 CA151610
6 · The paper itself

Abstract

backgroundCancer-associated fibroblasts (CAFs) are the predominant residents in the breast tumor microenvironment. In our work, we found activation of DNA damage-independent ATM (oxidized ATM), enhanced glycolysis and aberrant metabolism-associated gene expressions in breast CAFs. Nevertheless, whether and how oxidized ATM regulates the glycolytic activity of CAFs keep in unveil. Recently, a reverse Warburg effect was observed in tumor tissues, in which host cells (such as CAFs, PSCs) in the tumor microenvironment have been found to "fuel" the cancer cells via metabolites transfer. However, the molecular mechanisms of the metabolites from stromal cells playing a role to the progression of cancer cells remain to be determined.

methodsOxidized ATM activation in stromal CAFs was assessed by western blotting and immunofluorescence. The increased glycolytic ability of CAFs was validated by measurements of OCR and ECAR and detections of glucose consumption and lactate production. Kinase assay and western blotting were performed to confirm the phosphorylation of GLUT1. The membrane location of phosphorylated GLUT1 was determined by biotin pull-down assay and immunofluorescence staining. The regulation of PKM2 through oxidized ATM was evaluated by western blots. In addition, the impact of lactate derived from hypoxic CAFs on cancer cell invasion was investigated both in vitro (transwell assays, western blots) and in vivo (orthotopic xenografts).

findingsHypoxia-induced oxidized ATM promotes glycolytic activity of CAFs by phosphorylating GLUT1 at S490 and increasing PKM2 expression. Moreover, lactate derived from hypoxic CAFs, acting as a metabolic coupling between CAFs and breast cancer cells, promotes breast cancer cell invasion by activating the TGFβ1/p38 MAPK/MMP2/9 signaling axis and fueling the mitochondrial activity in cancer cells.

interpretationOur work shows that oxidized ATM-mediated glycolysis enhancement in hypoxic stromal fibroblasts plays an essential role in cancer cell invasion and metastasis and may implicate oxidized ATM as a target for breast tumor treatment. FUND: This research was supported by National Natural Science Foundation of China.

Indexed as

AnimalsAtaxia Telangiectasia Mutated ProteinsBreast NeoplasmsCancer-Associated FibroblastsCarrier ProteinsCell HypoxiaCell MovementCells, CulturedFemaleGlucoseGlucose Transporter Type 1GlycolysisHumansLactic AcidMembrane ProteinsMiceAtaxia Telangiectasia Mutated ProteinsCarrier ProteinsGlucoseGlucose Transporter Type 1Lactic AcidMembrane ProteinsRNA, Small InterferingThyroid Hormone-Binding ProteinsThyroid HormonesCAFsGLUT1HypoxiaOxidized-ATMPKM2(PYKM2)

Identifiers

PMID30799198
PMCPMC6442874
OpenAlexW2916881440

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.