Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast
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Research Article Cell biology Oncology

Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis

Abstract

Current therapies to treat non–small cell lung carcinoma (NSCLC) have proven ineffective owing to transient, variable, and incomplete responses. Here we show that ABL kinases, ABL1 and ABL2, promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses NSCLC metastasis to brain and bone, and other organs. ABL kinases are required for expression of prometastasis genes. Notably, ABL1 and ABL2 depletion impairs extravasation of lung adenocarcinoma cells into the lung parenchyma. We found that ABL-mediated activation of the TAZ and β-catenin transcriptional coactivators is required for NSCLC metastasis. ABL kinases activate TAZ and β-catenin by decreasing their interaction with the β-TrCP ubiquitin ligase, leading to increased protein stability. High-level expression of ABL1, ABL2, and a subset of ABL-dependent TAZ- and β-catenin–target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature.

Authors

Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast

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Figure 4

ABL kinases promote tumor cell extravasation into the lung parenchyma.

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ABL kinases promote tumor cell extravasation into the lung parenchyma. (...
(A) PC9 cells transduced with lentiviruses encoding either scrambled (SCR) or ABL1/ABL2-specific (AA) shRNAs were labeled with CellTracker Green and then injected into nude mice through the tail vein. Lung vessels were stained with rhodamine-conjugated lectin by tail vein injection 5 minutes before sacrificing mice. Lung cancer cells extravasated into the lung were counted 24 hours after injection. Representative images are shown. (B) Quantification of extravasated PC9 cells in the lungs (150-μm sections, n = 10 for each mouse) for indicated mice (SCR n = 4, AA n = 5). Data are represented as mean ± SEM. The P values were determined by Student’s t test. (C) Clusters of lung cancer cells extravasated into the lung parenchyma were imaged to visualize orthogonal views. Representative images are shown. (D) Depletion of ABL1 and ABL2 proteins was confirmed by Western blotting; p-CrkL is indicative of ABL kinase activity. All scale bars: 20 μm.