Binding blockade between TLN1 and integrin β1 represses triple-negative breast cancer

  1. Yixiao Zhang
  2. Lisha Sun  Is a corresponding author
  3. Haonan Li
  4. Liping Ai
  5. Qingtian Ma
  6. Xinbo Qiao
  7. Jie Yang
  8. Hao Zhang
  9. Xunyan Ou
  10. Yining Wang
  11. Guanglei Chen
  12. Jinqi Xue
  13. Xudong Zhu
  14. Yu Zhao
  15. Yongliang Yang  Is a corresponding author
  16. Caigang Liu  Is a corresponding author
  1. Shengjing Hospital of China Medical University, China
  2. Dalian University of Technology, China
  3. Mayo Clinic, United States

Abstract

Background: Integrin family are known as key gears in focal adhesion for triple-negative breast cancer (TNBC) metastasis. However, the integrin independent factor TLN1 remains vague in TNBC.

Methods: Bioinformatics analysis was performed based on TCGA database and Shengjing Hospital cohort. Western blot and RT-PCR were used to detect the expression of TLN1 and integrin pathway in cells. A small-molecule C67399 was screened for blocking TLN1 and integrin β1 through a novel computational screening approach by targeting the protein-protein binding interface. Drug pharmacodynamics were determined through xenograft assay.

Results: Upregulation of TLN1 in TNBC samples correlates with metastasis and worse prognosis. Silencing TLN1 in TNBC cells significantly attenuated the migration of tumour cells through interfering the dynamic formation of focal adhesion with integrin β1, thus regulating FAK-AKT signal pathway and epithelial-mesenchymal transformation. Targeting the binding between TLN1 and integrin β1 by C67399 could repress metastasis of TNBC.

Conclusions: TLN1 overexpression contributes to TNBC metastasis and C67399 targeting TLN1 may hold promise for TNBC treatment.

Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81872159, 81902607, 81874301), Liaoning Colleges Innovative Talent Support Program (Name: Cancer Stem Cell Origin and Biological Behaviour), Outstanding Scientific Fund of Shengjing Hospital (201803) and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Yixiao Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  2. Lisha Sun

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    For correspondence
    sunlisha1224@126.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4095-5026
  3. Haonan Li

    School of Bioengineering, Dalian University of Technology, Dalian, China
    Competing interests
    No competing interests declared.
  4. Liping Ai

    Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  5. Qingtian Ma

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  6. Xinbo Qiao

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6759-921X
  7. Jie Yang

    Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  8. Hao Zhang

    Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  9. Xunyan Ou

    Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  10. Yining Wang

    Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  11. Guanglei Chen

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  12. Jinqi Xue

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  13. Xudong Zhu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
  14. Yu Zhao

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  15. Yongliang Yang

    School of Bioengineering, Dalian University of Technology, Dalian, China
    For correspondence
    everbright99@foxmail.com
    Competing interests
    No competing interests declared.
  16. Caigang Liu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    For correspondence
    angel-s205@163.com
    Competing interests
    Caigang Liu, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3729-2839

Funding

National Natural Science Foundation of China (81872159)

  • Caigang Liu

Liaoning Colleges Innovative Talent Support Program (Cancer Stem Cell Origin and Biological Behavior)

  • Caigang Liu

Outstanding Scientific Fund of Shengjing Hospital (201803)

  • Caigang Liu

Outstanding Young Scholars of Liaoning Province (2019-YQ-10)

  • Caigang Liu

National Natural Science Foundation of China (81902607)

  • Yixiao Zhang

National Natural Science Foundation of China (81874301)

  • Yongliang Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Renata Pasqualini, Rutgers University, United States

Ethics

Animal experimentation: The current study was approved by the institutional research ethics committee of Shengjing Hospital of China Medical University (Project identification code: 2018PS304K, date on 03/05/2018), and each participant signed an informed consent before being included in the study. Meanwhile, this study was performed in very strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering of the animals, and all the animals were handled according to approved Animal Ethics and Experimentation Committee protocols of Shengjing Hospital of China Medical University (Project identification code: 2018PS312K, date on 03/05/2018).

Human subjects: Written informed consent was obtained from all the patients, and this study was approved by the institutional research ethics committee of China Medical University

Version history

  1. Received: March 17, 2021
  2. Accepted: March 7, 2022
  3. Accepted Manuscript published: March 14, 2022 (version 1)
  4. Version of Record published: March 21, 2022 (version 2)

Copyright

© 2022, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,193
    Page views
  • 208
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yixiao Zhang
  2. Lisha Sun
  3. Haonan Li
  4. Liping Ai
  5. Qingtian Ma
  6. Xinbo Qiao
  7. Jie Yang
  8. Hao Zhang
  9. Xunyan Ou
  10. Yining Wang
  11. Guanglei Chen
  12. Jinqi Xue
  13. Xudong Zhu
  14. Yu Zhao
  15. Yongliang Yang
  16. Caigang Liu
(2022)
Binding blockade between TLN1 and integrin β1 represses triple-negative breast cancer
eLife 11:e68481.
https://doi.org/10.7554/eLife.68481

Share this article

https://doi.org/10.7554/eLife.68481

Further reading

    1. Medicine
    2. Neuroscience
    Marvin Petersen, Felix Hoffstaedter ... Bastian Cheng
    Research Article

    The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis, we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

    1. Cancer Biology
    2. Medicine
    Won Yeong Park, Jieun Yun ... Ki Hean Kim
    Research Article

    Nondestructive pathology based on three-dimensional (3D) optical microscopy holds promise as a complement to traditional destructive hematoxylin and eosin (H&E) stained slide-based pathology by providing cellular information in high throughput manner. However, conventional techniques provided superficial information only due to shallow imaging depths. Herein, we developed open-top two-photon light sheet microscopy (OT-TP-LSM) for intraoperative 3D pathology. An extended depth of field two-photon excitation light sheet was generated by scanning a nondiffractive Bessel beam, and selective planar imaging was conducted with cameras at 400 frames/s max during the lateral translation of tissue specimens. Intrinsic second harmonic generation was collected for additional extracellular matrix (ECM) visualization. OT-TP-LSM was tested in various human cancer specimens including skin, pancreas, and prostate. High imaging depths were achieved owing to long excitation wavelengths and long wavelength fluorophores. 3D visualization of both cells and ECM enhanced the ability of cancer detection. Furthermore, an unsupervised deep learning network was employed for the style transfer of OT-TP-LSM images to virtual H&E images. The virtual H&E images exhibited comparable histological characteristics to real ones. OT-TP-LSM may have the potential for histopathological examination in surgical and biopsy applications by rapidly providing 3D information.