Highlights of This Issue Free

Brain metastasis from breast cancer is a growing problem, due in part to improved therapies for metastatic disease and the inability of many drugs to cross the blood-brain barrier. McGowan and colleagues investigated the role of cancer stem-like cells and a potential regulator, Notch, on the formation of brain metastases by using a γ-secretase inhibitor and specific Notch1 silencing. Cells with a reduced stem-like phenotype formed fewer metastases. Notch1 shRNA or DAPT treatment reduced the proportion of stemlike cells and the number of metastases formed in vivo. These data suggest that the cancer stem cell phenotype contributes to the development of brain metastases from breast cancer and that this may arise in part from increased Notch activity.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy with ineffective treatments and dismal survival rates. To expedite biological testing of putative PDAC metastasis genes, Muniz and coworkers developed a new mouse tumor model that uses intracardiac injections of pancreatic cancer cells and bioluminescence imaging to track tumor dissemination and development in vivo. The model was validated by using the p14ARF tumor suppressor, which acted independently of p53 to inhibit PDAC tumor cell invasiveness and colonization in vivo. These findings establish a unique platform for rapidly identifying genetic events controlling pancreatic cancer metastasis, defining new PDAC targets, and testing innovative therapies.

In this study, Shultz and colleagues explore the molecular mechanisms that regulate caspase 9 RNA splicing as well as the biological relevance of this mechanism in the treatment of non–small cell lung cancer (NSCLC). Specifically, a novel intronic splicing enhancer, C9-I6/ISE, was identified and shown to interact with the RNA trans-factor, SRSF1. Furthermore, the direct manipulation of caspase 9 RNA splicing played a key role in the chemotherapy sensitivity of NSCLC cells to individual agents and the synergism of the clinically relevant agents, daunorubicin and erlotinib. Hence, this molecular splicing mechanism is a relevant therapeutic target for NSCLC.

Medulloblastoma is the most common malignant brain tumor in children and is associated with poor prognosis in high-risk patients. In this study, Guerreiro and colleagues have used a high-throughput RNA interference screen to identify novel molecular targets in medulloblastoma cell lines. Our results show for the first time that the phosphoinositide 3-kinase (PI3K) isoform p110γ plays a crucial role in the proliferation and chemoresistance of medulloblastoma cells. In addition, p110γ was found to be overexpressed in primary medulloblastoma samples and cell lines. The PI3K isoform p110γ, therefore, represents a potential novel drug target in medulloblastoma.