1. Cancer Biology

Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models

  1. Emily R Webb  Is a corresponding author
  2. Georgia L Dodd
  3. Michaela Noskova
  4. Esme Bullock
  5. Morwenna Muir
  6. Margaret C Frame
  7. Alan Serrels
  8. Valerie G Brunton  Is a corresponding author
  1. University of Edinburgh, United Kingdom
https://doi.org/10.7554/eLife.85739
Share this article
Cite this article
  1. Emily R Webb
  2. Georgia L Dodd
  3. Michaela Noskova
  4. Esme Bullock
  5. Morwenna Muir
  6. Margaret C Frame
  7. Alan Serrels
  8. Valerie G Brunton
(2023)
Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models
eLife 12:e85739.
https://doi.org/10.7554/eLife.85739
  2. Download BibTeX
  3. Download .RIS

Abstract

The adhesion protein Kindlin-1 is over-expressed in breast cancer where it is associated with metastasis-free survival; however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in mouse models of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells led to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of spontaneous mammary tumorigenesis. There was a significant increase in IL-6 secretion from Met-1 cells when Kindlin-1 was depleted and conditioned media from Kindlin-1-depleted cells led to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6. In addition, deletion of tumor-derived IL-6 in the Kindlin-1-depleted tumors reversed the reduction of tumor-infiltrating Tregs. Overall, these data identify a novel function for Kindlin-1 in regulation of anti-tumor immunity, and that Kindlin-1 dependent cytokine secretion can impact the tumor immune environment.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 2, 4, 5 and 6

The following previously published data sets were used

Article and author information

Author details

  1. Emily R Webb

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Emily.webb@ed.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9339-4544

  2. Georgia L Dodd

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  3. Michaela Noskova

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  4. Esme Bullock

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  5. Morwenna Muir

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  6. Margaret C Frame

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    Margaret C Frame, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5882-1942

  7. Alan Serrels

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4992-6077

  8. Valerie G Brunton

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    v.brunton@ed.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7778-8794

Funding

Cancer Research UK (C157/A24837)

  • Emily R Webb

Cancer Research UK (C157/A29279)

  • Emily R Webb
  • Georgia L Dodd
  • Michaela Noskova
  • Esme Bullock
  • Morwenna Muir
  • Margaret C Frame
  • Alan Serrels
  • Valerie G Brunton

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

Ethics

Animal experimentation: All experiments were carried out in compliance with UK Home Office regulations underproject licence PP7510272. All animal procedures were approved by the University of Edinburgh Animal Welfare & Ethical Review Body (AWERB) approval PL05-21, and in accordance with the principles of the 3Rs. Every effort was made to minimise suffering.

Copyright

© 2023, Webb 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

  • 1,165
    views
  • 204
    downloads
  • 8
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Emily R Webb
  2. Georgia L Dodd
  3. Michaela Noskova
  4. Esme Bullock
  5. Morwenna Muir
  6. Margaret C Frame
  7. Alan Serrels
  8. Valerie G Brunton
(2023)
Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models
eLife 12:e85739.
https://doi.org/10.7554/eLife.85739

Share this article

https://doi.org/10.7554/eLife.85739

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    Changes in local mineral homeostasis facilitate the formation of benign and malignant testicular microcalcifications

    Ida Marie Boisen, Nadia Krarup Knudsen ... Martin Blomberg Jensen
    Research Article

    Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but are also found in benign cases such as loss-of-function variants in the phosphate transporter SLC34A2. Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker Osteocalcin (gene name: Bglap, protein name). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins are associated with lower Slc34a2 and higher Bglap/Slc34a1 (protein name: NPT2a) expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express phosphate transporter NPT2a, Osteocalcin, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization inhibitor pyrophosphate. In conclusion, testicular microcalcifications arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.

    1. Cancer Biology

    TAK1-mediated phosphorylation of PLCE1 represses PIP2 hydrolysis to impede esophageal squamous cancer metastasis

    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.

    1. Cancer Biology
    2. Cell Biology

    Breast Cancer: How cell crowding causes cancer cells to spread

    Rui Hua, Jean X Jiang
    Insight

    Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.