Regulation of lung cancer metastasis by Klf4-numb-like signaling

Valentina Vaira, Alice Faversani, Nina Martin, David S. Garlick, Stefano Ferrero, Mario Nosotti, Joseph L. Kissil, Silvano Bosari, Dario C. Altieri

Research output: Contribution to journalArticle

Abstract

Metastatic traits seem to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer.

Original languageEnglish (US)
Pages (from-to)2695-2705
Number of pages11
JournalCancer Research
Volume73
Issue number8
DOIs
StatePublished - Apr 15 2013
Externally publishedYes

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Lung Neoplasms
Neoplasm Metastasis
Neoplasms
Stem Cells
Anoikis
MicroRNAs
Non-Small Cell Lung Carcinoma
Cell Movement
Carcinogenesis
Transcription Factors
Survival
Therapeutics
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Vaira, V., Faversani, A., Martin, N., Garlick, D. S., Ferrero, S., Nosotti, M., ... Altieri, D. C. (2013). Regulation of lung cancer metastasis by Klf4-numb-like signaling. Cancer Research, 73(8), 2695-2705. https://doi.org/10.1158/0008-5472.CAN-12-4232

Regulation of lung cancer metastasis by Klf4-numb-like signaling. / Vaira, Valentina; Faversani, Alice; Martin, Nina; Garlick, David S.; Ferrero, Stefano; Nosotti, Mario; Kissil, Joseph L.; Bosari, Silvano; Altieri, Dario C.

In: Cancer Research, Vol. 73, No. 8, 15.04.2013, p. 2695-2705.

Research output: Contribution to journalArticle

Vaira, V, Faversani, A, Martin, N, Garlick, DS, Ferrero, S, Nosotti, M, Kissil, JL, Bosari, S & Altieri, DC 2013, 'Regulation of lung cancer metastasis by Klf4-numb-like signaling', Cancer Research, vol. 73, no. 8, pp. 2695-2705. https://doi.org/10.1158/0008-5472.CAN-12-4232
Vaira V, Faversani A, Martin N, Garlick DS, Ferrero S, Nosotti M et al. Regulation of lung cancer metastasis by Klf4-numb-like signaling. Cancer Research. 2013 Apr 15;73(8):2695-2705. https://doi.org/10.1158/0008-5472.CAN-12-4232
Vaira, Valentina ; Faversani, Alice ; Martin, Nina ; Garlick, David S. ; Ferrero, Stefano ; Nosotti, Mario ; Kissil, Joseph L. ; Bosari, Silvano ; Altieri, Dario C. / Regulation of lung cancer metastasis by Klf4-numb-like signaling. In: Cancer Research. 2013 ; Vol. 73, No. 8. pp. 2695-2705.
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