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

Dian Yang,Jing Shan Lim,Fangfei Qu,Chen-Hua Chuang,Barbara M Grüner,Christina Kong,Monte M Winslow,Nadine Jahchan,Julien Sage,Madeleine J Oudin,Hongchen Cai,Christin S Kuo

doi:10.7554/elife.50616

Dian Yang, Jing Shan Lim + Show 10 more

Open Access

https://doi.org/10.7554/elife.50616

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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.

Highlights

Metastases are a major cause of cancer-related morbidity and mortality
To investigate Small cell lung carcinoma (SCLC) migration, we developed an assay in which SCLC cells, which classically grow in culture as floating spheres or aggregates, are grown as a monolayer under
SCLC cell lines (N2N1G, 16T, 6PF) derived from the Rb f/f;p53f/f (DKO) and Rb f/f;p53 f/f;p130 f/f (TKO) genetically engineered mouse models form long cellular protrusions into cell-free spaces (Figure 1A-B). To determine whether these structures project into cell-free areas or they exist within monolayers, we cultured a minor fraction of fluorescently-labeled, GFPpositive SCLC cells with control SCLC cells

Summary

Introduction

By the time cancer cells leave their primary site and spread to distant sites, they have acquired the ability to migrate and invade, as well as characteristics that enable them to survive and proliferate within new microenvironments. These phenotypes are likely driven by changes in gene expression and epigenetic programs that allow cancer cells to overcome the many hurdles that normally constrain the metastatic process. The ability of SCLC cells to leave the primary tumor and establish inoperable metastases is a major cause of death and a serious impediment to successful therapy (Farago and Keane, 2018, van Meerbeeck et al, 2011). SCLC is one of the most metastatic human cancers, with over

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