Axon-like protrusions promote small cell lung cancer migration and metastasis

  1. Dian Yang
  2. Fangfei Qu
  3. Hongchen Cai
  4. Chen-Hua Chuang
  5. Jing Shan Lim
  6. Nadine Jahchan
  7. Barbara M Grüner
  8. Christin S Kuo
  9. Christina Kong
  10. Madeleine J Oudin
  11. Monte M Winslow  Is a corresponding author
  12. Julien Sage  Is a corresponding author
  1. Stanford University School of Medicine, United States
  2. Tufts University, United States

Abstract

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

Data availability

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

The following previously published data sets were used

Article and author information

Author details

  1. Dian Yang

    Cancer Biology Program, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  2. Fangfei Qu

    Department of Pediatrics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  3. Hongchen Cai

    Department of Genetics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  4. Chen-Hua Chuang

    Department of Genetics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  5. Jing Shan Lim

    Cancer Biology Program, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  6. Nadine Jahchan

    Department of Pediatrics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  7. Barbara M Grüner

    Department of Genetics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0974-4826
  8. Christin S Kuo

    Department of Pediatrics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  9. Christina Kong

    Department of Pathology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  10. Madeleine J Oudin

    Department of Biomedical Engineering, Tufts University, Medford, United States
    Competing interests
    No competing interests declared.
  11. Monte M Winslow

    Cancer Biology Program, Stanford University School of Medicine, Stanford, United States
    For correspondence
    mwinslow@stanford.edu
    Competing interests
    No competing interests declared.
  12. Julien Sage

    Cancer Biology Program, Stanford University School of Medicine, Stanford, United States
    For correspondence
    julsage@stanford.edu
    Competing interests
    Julien Sage, receives research funding from Stemcentrx/Abbvie, Pfizer, and Revolution Medicines and owns stock in Forty Seven Inc.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8928-9968

Funding

National Cancer Institute (NIH R01 CA206540)

  • Julien Sage

National Cancer Institute (P30 CA124435)

  • Monte M Winslow
  • Julien Sage

Tobacco-Related Disease Research Program (24DT-0001)

  • Dian Yang

Damon Runyon Cancer Research Foundation

  • Fangfei Qu

Tobacco-Related Disease Research Program

  • Hongchen Cai

American Lung Association

  • Chen-Hua Chuang

Pancreatic Cancer Action Network

  • Barbara M Grüner

Hope Funds for Cancer Research

  • Barbara M Grüner

National Cancer Institute (R00 CA207866)

  • Madeleine J Oudin

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 performed in accordance with Stanford University Institutional Animal Care and Use Committee guidelines (protocol number 13565).

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: July 27, 2019
  2. Accepted: December 13, 2019
  3. Accepted Manuscript published: December 13, 2019 (version 1)
  4. Version of Record published: January 2, 2020 (version 2)

Copyright

© 2019, Yang 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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  1. Dian Yang
  2. Fangfei Qu
  3. Hongchen Cai
  4. Chen-Hua Chuang
  5. Jing Shan Lim
  6. Nadine Jahchan
  7. Barbara M Grüner
  8. Christin S Kuo
  9. Christina Kong
  10. Madeleine J Oudin
  11. Monte M Winslow
  12. Julien Sage
(2019)
Axon-like protrusions promote small cell lung cancer migration and metastasis
eLife 8:e50616.
https://doi.org/10.7554/eLife.50616

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