Abstract

Over half of breast cancer related deaths are due to recurrence five or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.

Data availability

Sequencing data have been deposited in SRA as PRJNA506006 for cell line data and PRJNA505845 for macrophage data.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Andrea Walens

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    For correspondence
    andrea.walens@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Ashley V DiMarco

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryan Lupo

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Benjamin R Kroger

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeffrey S Damrauer

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8148-0285
  6. James V Alvarez

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    For correspondence
    james.alvarez@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2910-7621

Funding

National Cancer Institute (F31 CA220957)

  • Andrea Walens

National Cancer Institute (R01 CA208042)

  • James V Alvarez

Duke University School of Medicine

  • James V Alvarez

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 animal experiments were performed with approval from the Duke institutional animal care and use committee (IACUC) under Protocol #A199-17-08 and in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Mice were housed under barrier conditions with standard 12-hour light/dark hours, and fed standard chow.

Copyright

© 2019, Walens 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

  • 5,672
    views
  • 765
    downloads
  • 148
    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. Andrea Walens
  2. Ashley V DiMarco
  3. Ryan Lupo
  4. Benjamin R Kroger
  5. Jeffrey S Damrauer
  6. James V Alvarez
(2019)
CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors
eLife 8:e43653.
https://doi.org/10.7554/eLife.43653

Share this article

https://doi.org/10.7554/eLife.43653

Further reading

    1. Cancer Biology
    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
    Xiangning Bu, Nathanael Ashby ... Inhee Chung
    Research Article

    Cell crowding is a common microenvironmental factor influencing various disease processes, but its role in promoting cell invasiveness remains unclear. This study investigates the biomechanical changes induced by cell crowding, focusing on pro-invasive cell volume reduction in ductal carcinoma in situ (DCIS). Crowding specifically enhanced invasiveness in high-grade DCIS cells through significant volume reduction compared to hyperplasia-mimicking or normal cells. Mass spectrometry revealed that crowding selectively relocated ion channels, including TRPV4, to the plasma membrane in high-grade DCIS cells. TRPV4 inhibition triggered by crowding decreased intracellular calcium levels, reduced cell volume, and increased invasion and motility. During this process, TRPV4 membrane relocation primed the channel for later activation, compensating for calcium loss. Analyses of patient-derived breast cancer tissues confirmed that plasma membrane-associated TRPV4 is specific to high-grade DCIS and indicates the presence of a pro-invasive cell volume reduction mechanotransduction pathway. Hyperosmotic conditions and pharmacologic TRPV4 inhibition mimicked crowding-induced effects, while TRPV4 activation reversed them. Silencing TRPV4 diminished mechanotransduction in high-grade DCIS cells, reducing calcium depletion, volume reduction, and motility. This study uncovers a novel pro-invasive mechanotransduction pathway driven by cell crowding and identifies TRPV4 as a potential biomarker for predicting invasion risk in DCIS patients.