Molecular Pathway Decreases Cell Adhesion and Initiates Metastasis

A recent paper outlined a molecular pathway that enables lung cancer cells to migrate away from the site of the primary tumor and become established in other parts of the body.

Investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) linked a virtual alphabet soup of genes and their protein products to the epithelial-to-mesenchymal transition (EMT) that is a prerequisite for metastasis.

The serine/threonine kinase LKB1 (liver kinase B1) is a tumor suppressor gene whose loss is associated with increased metastatic potential. In an effort to define biochemical signatures of metastasis associated with LKB1 loss, the investigators discovered that the EMT transcription factor Snail1 was uniquely upregulated upon LKB1 deficiency across cell types. Snail1 is a central regulator of epithelial cell adhesion and movement in EMTs during embryo development; a process reactivated during cancer metastasis. The ability of LKB1 to suppress Snail1 levels was independent of AMPK (AMP-activated protein kinase) but required the related kinases MARK1 (MAP/microtubule affinity-regulating kinase 1) and MARK4 (MAP/microtubule affinity-regulating kinase 4).

In a screen for substrates of the kinases involved in Snail regulation, the investigators identified the scaffolding protein DIXDC1 (DIX domain containing 1), a positive regulator of the Wnt signaling pathway that is associated with gamma tubulin at the centrosome. Similar to loss of LKB1, DIXDC1 depletion resulted in upregulation of Snail1 in a FAK (Focal Adhesion Kinase)-dependent manner, leading to increased cell invasion. FAK is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes. It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.

MARK1 phosphorylation of DIXDC1 was required for its localization to focal adhesions and ability to suppress metastasis in mice. DIXDC1 is frequently downregulated in human cancers, which correlates with poor survival.

"Lung cancer, even when it is discovered early, is often able to metastasize almost immediately and take hold throughout the body," said senior author Dr. Reuben J. Shaw, professor of molecular and cell biology at the Salk Institute for Biological Studies. "The reason behind why some tumors do that and others do not has not been very well understood. Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive. The good news is that this finding predicts that patients missing either gene should be sensitive to new therapies targeting focal adhesion enzymes, which are currently being tested in early-stage clinical trials."

The study was published in the July 17, 2014, online edition of the journal Molecular Cell.

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Salk Institute for Biological Studies