2024-03-29T05:43:52Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1346782018-09-27T06:59:34Zcom_10261_112com_10261_1col_10261_365
DIGITAL.CSIC
author
Antón, Iker
author
Guruceaga, Elizabeth
author
Vicent, Silvestre
author
De Las Rivas, Javier
author
Lecanda, Fernando
funder
Red Temática de Investigación Cooperativa en Cáncer (España)
funder
Instituto de Salud Carlos III
funder
Nafarroako Gobernua
funder
Ministerio de Ciencia e Innovación (España)
funder
Fundación "la Caixa"
2016-07-12T07:09:17Z
2016-07-12T07:09:17Z
2014
Oncogene 33(43): 5090-5099 (2014)
http://hdl.handle.net/10261/134678
10.1038/onc.2013.440
http://dx.doi.org/10.13039/501100004587http://dx.doi.org/10.13039/501100004837
Bone metastasis of lung adenocarcinoma (AC) is a frequent complication of advanced disease. The purpose of this study was to identify key mediators conferring robust prometastatic activity with clinical significance. We isolated highly metastatic subpopulations (HMS) using a previously described in vivo model of lung AC bone metastasis. We performed transcriptomic profiling of HMS and stringent bioinformatics filtering. Functional validation was assessed by overexpression and lentiviral silencing of single, double and triple combination in vivo and in vitro. We identified HDAC4, PITX1 and ROBO1 that decreased bone metastatic ability after their simultaneous abrogation. These effects were solely linked to defects in osseous colonization. The molecular mechanisms related to bone colonization were mediated by non-cell autonomous effects that include the following: (1) a marked decrease in osteoclastogenic activity in vitro and in vivo, an effect associated with reduced pro-osteoclastogenic cytokines IL-11 and PTHrP expression levels, as well as decreased in vitro expression of stromal rankl in conditions mimicking tumor-stromal interactions; (2) an abrogated response to TGF-β signaling by decreased phosphorylation and levels of Smad2/3 in tumor cells and (3) an impaired metalloproteolytic activity in vitro. Interestingly, coexpression of HDAC4 and PITX1 conferred high prometastatic activity in vivo. Further, levels of both genes correlated with patients at higher risk of metastasis in a clinical lung AC data set and with a poorer clinical outcome. These findings provide functional and clinical evidence that this metastatic subset is an important determinant of osseous colonization. These data suggest novel therapeutic targets to effectively block lung AC bone metastasis.
eng
closedAccess
PITX1
HDAC4
ROBO1
Osteoclastogenesis
Outcome
Microenvironment
MMP
A gene signature of bone metastatic colonization sensitizes for tumor-induced osteolysis and predicts survival in lung cancer
artículo
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URL
https://digital.csic.es/bitstream/10261/134678/1/accesoRestringido.pdf
File
MD5
42637ae8545636bc41605c1740a9a84e
15753
application/pdf
accesoRestringido.pdf