Chan et al. reveal that the focal adhesion kinase (FAK) coordinates these processes to permit forward movement. The study will be published online April 13 (www.jcb) and will appear in the April 20 print issue of the Journal of Cell Biology.

Crawling cancer cells send out extensions called invadopodia. By releasing enzymes that dissolve the extracellular matrix (ECM), invadopodia clear a path for the cell to wriggle through. As they move, cancer cells get traction by temporarily attaching to the ECM through focal adhesions. FAK spurs focal adhesions to disengage, and it is more abundant in metastatic tumors. Whether FAK also regulates invadopodia was unknown.

When Chan et al. removed FAK, breast cancer cells were much less invasive. But to the team's surprise, the FAK-lacking cells sprouted extra invadopodia. The cells also sported large focal adhesions that were particularly sticky. The protein Src serves as FAK's helper. FAK and Src work together to phosphorylate tyrosines in proteins such as paxillin, which then disassemble the focal adhesion. But the team found that in cells missing FAK, the phosphorylated proteins accumulated in invadopodia. Src's localization reflects this difference. In control cells, Src accumulated in focal adhesions. In FAK's absence, Src headed to the invadopodia.

The work suggests that FAK controls movement by balancing the number of invadopodia that create a path for migration and the number of focal adhesions that hold the cell back. The next question, the researchers say, is how FAK and Src integrate these events to promote invasion.

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For this study, Anderson and his multi-institutional team collected biological samples from numerous multigenerational families with five or more members who were affected by lung cancer. Through a combination of what is known as "fine mapping"-where genetic information is dissected and analyzed-and genetic association studies, researchers identified RGS17 as a major candidate susceptibility gene for familial lung cancers.

Research has shown that lung cancer can occur sporadically-where people have no known risk factors or family history-or hereditarily, occurring in multiple members of the same family. In 2004, Anderson's team reported the first genetic evidence of a major lung cancer "susceptibility locus" on chromosome 6, and evidence of a susceptibility region on three other chromosomes.

The region of the original chromosome where the lung cancer markers were found contained about 100 genes, including several genes suspected to be involved in tumor suppression and cell growth.

Using a genetically altered mouse model, researchers determined that when RGS17 was suppressed, lung tumors shrank, proving the gene was involved in cancer development and must be present for cancer growth.

"What was most interesting is that this same gene was over-expressed in 60 percent of the samples from non-hereditary lung tumors," explains Anderson. "This suggests that perhaps epigenetic factors may be contributing to abnormal genetic development."

The UC-led team will conduct additional research to investigate how environmental factors may influence familial cancer development.

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