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

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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

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Article and author information

Author details

Dian Yang

Cancer Biology Program, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Fangfei Qu

Department of Pediatrics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Hongchen Cai

Department of Genetics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Chen-Hua Chuang

Department of Genetics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Jing Shan Lim

Cancer Biology Program, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Nadine Jahchan

Department of Pediatrics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Barbara M Grüner

Department of Genetics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0974-4826
Christin S Kuo

Department of Pediatrics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Christina Kong

Department of Pathology, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Madeleine J Oudin

Department of Biomedical Engineering, Tufts University, Medford, United States

Competing interests
No competing interests declared.
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.
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.

"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).

Copyright

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.