1. Cancer Biology
  2. Cell Biology
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DDR2 controls breast tumor stiffness and metastasis by regulating Integrin mediated mechanotransduction in CAFs

Research Article
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Cite this article as: eLife 2019;8:e45508 doi: 10.7554/eLife.45508

Abstract

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors in vivo, was found to influence mechanotransduction by controlling full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment. The action of DDR2 in tumor CAFs is thus critical for remodeling collagen fibers at the tumor-stromal boundary to generate a physically permissive tumor microenvironment for tumor cell invasion and metastases.

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. Samantha VH Bayer

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Whitney R Grither

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Audrey Brenot

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Priscilla Y Hwang

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Craig E Barcus

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Melanie Ernst

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8995-3507
  7. Patrick Pence

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christopher Walter

    Department of Mechanical Engineering, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Amit Pathak

    Department of Mechanical Engineering, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gregory D Longmore

    ICCE Institute, Washington University in St Louis, St Louis, United States
    For correspondence
    glongmore@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7568-8151

Funding

National Institute for Health Research (R01 CA196205)

  • Gregory D Longmore

National Institute for Health Research (R01 CA223758)

  • Gregory D Longmore

National Institute for Health Research (U54 CA210173)

  • Gregory D Longmore

American Cancer Society (131342-PF-17-238-01-CSM)

  • Priscilla Y Hwang

National Institute for Health Research (F30 CA200386)

  • Samantha VH Bayer

National Institute for Health Research (T32 GM07200)

  • Samantha VH Bayer
  • Whitney R Grither

National Institute for Health Research (T32 CA113275)

  • Craig E Barcus

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health under protocol #20150145.

Reviewing Editor

  1. Joan Massagué, Memorial Sloan-Kettering Cancer Center, United States

Publication history

  1. Received: January 24, 2019
  2. Accepted: May 29, 2019
  3. Accepted Manuscript published: May 30, 2019 (version 1)
  4. Version of Record published: June 7, 2019 (version 2)

Copyright

© 2019, Bayer 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.

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Further reading

    1. Cancer Biology
    2. Medicine
    Shuhua Cheng et al.
    Research Article

    Background:

    Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma, not otherwise specified (PTCL-NOS), remains poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking.

    Methods:

    We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and 2 with PTCL-NOS.

    Results:

    Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥ 2 pathogenic TET2 variants with ≥ 15% of allele burden conferred higher risk for CHN (P = 0.0006, hazard ratio = 14.01, PPV=88.9%, NPV=92.1%).

    Conclusion:

    We provided genetic evidence that AITL/PTCL-NOS, CH, CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients.

    Funding:

    R01 grant (CA194547) from the National Cancer Institute to WT.

    1. Cancer Biology
    Teresa WM Fan et al.
    Research Article Updated

    Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with 13C6-Glc/13C5,15N2-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1+ lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.