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 language | English (US) |
|---|---|
| Pages (from-to) | 2695-2705 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 73 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - Regulation of lung cancer metastasis by Klf4-numb-like signaling
AU - Vaira, Valentina
AU - Faversani, Alice
AU - Martin, Nina
AU - Garlick, David S.
AU - Ferrero, Stefano
AU - Nosotti, Mario
AU - Kissil, Joseph L.
AU - Bosari, Silvano
AU - Altieri, Dario C.
PY - 2013/4/15
Y1 - 2013/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84876901009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876901009&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-4232
DO - 10.1158/0008-5472.CAN-12-4232
M3 - Article
C2 - 23440423
AN - SCOPUS:84876901009
VL - 73
SP - 2695
EP - 2705
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 8
ER -