Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT

Srinivas Malladi, Danilo G. MacAlinao, Xin Jin, Lan He, Harihar Basnet, Yilong Zou, Elisa De Stanchina, Joan Massagué

Research output: Contribution to journalArticle

203 Scopus citations

Abstract

Metastasis frequently develops years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities through unknown mechanisms. We isolated latency competent cancer (LCC) cells from early stage human lung and breast carcinoma cell lines and defined the mechanisms that suppress outgrowth, support long-term survival, and maintain tumor-initiating potential in these cells during the latent metastasis stage. LCC cells show stem-cell-like characteristics and express SOX2 and SOX9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions. Through expression of the WNT inhibitor DKK1, LCC cells self-impose a slow-cycling state with broad downregulation of ULBP ligands for NK cells and evasion of NK-cell-mediated clearance. By expressing a Sox-dependent stem-like state and actively silencing WNT signaling, LCC cells can enter quiescence and evade innate immunity to remain latent for extended periods.

Original languageEnglish (US)
Pages (from-to)45-60
Number of pages16
JournalCell
Volume165
Issue number1
DOIs
StatePublished - Mar 24 2016

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Malladi, S., MacAlinao, D. G., Jin, X., He, L., Basnet, H., Zou, Y., De Stanchina, E., & Massagué, J. (2016). Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell, 165(1), 45-60. https://doi.org/10.1016/j.cell.2016.02.025