Highlights of This Issue

Epithelial-mesenchymal transition (EMT) has been implicated in the initial stages of metastasis. What remains unclear, however, is how it is maintained in late metastatic cells and whether it also regulates the subsequent dormant state of micrometastases. Tran and colleagues detail a mechanistic link between EMT and cancer dormancy in which Snail1 and Twist1, two key EMT inducers, cooperate with each other to initiate and maintain EMT, respectively, and in so doing Twist1 contributes directly to the cancer dormancy program. Therefore, Twist1 represents a potential therapeutic target to manipulate tumor dormancy for clinical benefits.

The transmembrane protein Trop2 has been reported to be overexpressed in carcinomas, but its function remains largely unknown. In an effort to elucidate its role in tumorigenesis, Wang and colleagues generated Trop2^−/− animals, which lack an obvious tumor phenotype. However, when mated into an Arf-null background and exposed to carcinogens, Trop2^−/− mice develop tumors with both squamous and spindle cell histology. Accordingly, immortalized cells from Trop2^−/− Arf^−/− mice show hyperactivation of MAPK and Src pathways. Additionally, poorly differentiated head and neck cancers exhibit low Trop2 levels. These results identify a tumor suppressor role and highlight unexpected signaling properties for this protein.

In this study, Azad and colleagues present the first report of DNA-dependent protein kinase (DNA-PK) blockade leading to accelerated senescence in irradiated human cancer cells. The study shows that DNAPK inhibition modulates repair of therapeutically induced DNA doublestrand breaks and thus promotes p53-dependent accelerated senescence in irradiated cells. Significantly, this report notes the lack of clinical trials using novel pharmacological inhibitors of DNA-PK in conjunction with ionizing radiation. Thus, these data provide a sound rationale for both preclinical and clinical evaluation of novel DNA-PK inhibitors in combination with ionizing radiation and other anticancer agents that induce doublestrand breaks or inhibit double-strand break repair.

Many strategies used to kill cancer cells induce stress-responses that inhibit treatment-induced cell death and promote emergence of a treatment resistant phenotype. Whereas both Y-box binding protein-1 (YB-1) and clusterin are known to confer taxane resistance in cancer, their mechanistic interrelationships are undefined. Shiota and colleagues found that many varied anticancer therapeutic agents including taxanes induce endoplasmic reticulum stress with activation of YB-1. YB-1 was shown to be a critical regulator of stress-induced clusterin transcription and expression, and clusterin was shown to play a dominant downstream mediator of YB-1 in stressinduced cytoprotection and paclitaxel resistance in prostate cancer cells.