Tumor Suppressor LKB1 Associated With Cancer Spread, New Study Suggests

Tumor Suppressor LKB1 Associated With Cancer Spread, New Study Suggests

lung cancer metastasizedThe serine-threonine kinase LKB1 is a tumor suppressor whose loss is associated with increased movement of cancer from the lungs to other parts of the body, a study published in the journal Molecular Cells suggests. “Lung cancer, even when it is discovered early, is often able to metastasize almost immediately and take hold throughout the body,” noted Reuben J. Shaw, a professor of molecular and cell biology at Salk Institute for Biological Studies in California.

Aiming to define biochemical signatures of metastasis associated with LKB1 loss, a group of researchers led by Jonathan M. Goodwin found that the epithelial-to-mesenchymal transition (a process by which epithelial cells lose their cell polarity, gaining migratory and invasive properties) transcription factor Snail1 (a repressor which down regulates the expression of ectodermal genes within the mesoderm) was uniquely upregulated upon LKB1 deficiency across cell types.

Furthermore, in a screen for substrates of the kinases MARK1 and MARK4 required for LKB1 to suppress Snail1 levels, the team identified the scaffolding protein DIXDC1. Similar to the loss of LKB1, DIXDC1 depletion results in upregulation of Snail1 in a FAK-dependent manner, leading to increased cell invasion.

These findings led researchers to define DIXDC1 as a new target for therapy, as this protein receives instructions from LKB1 to go to focal adhesions and change their size and number. When DIXDC1 is active, focal adhesions grow large and sticky, anchoring cells to their spot.

According to Goodwin, while DIXDC1 is inhibited in cancer and metastasis, the communication between LKB1 and DIXDC1 is responsible for a ‘stay-put’ signal in cells.

As a result, patients missing either gene should be sensitive to new therapies targeting focal adhesion enzymes, which are currently being tested in early-stage clinical trials.

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