Features | Partner Sites | Information | LinkXpress
Sign In
Demo Company

Molecular Pathway Decreases Cell Adhesion and Initiates Metastasis

By BiotechDaily International staff writers
Posted on 28 Jul 2014
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.

Related Links:

Salk Institute for Biological Studies


Drug Discovery

view channel
Image: Use of catchphrase terms like “breakthrough” and “promising” in public news media presenting new drugs tends to result in incorrect assumptions and conclusions about the meaning and significance of criteria for FDA breakthrough-designated and accelerated-approval drugs (Photo courtesy of Dartmouth Institute).

Words That Inappropriately Enhance Perception of New Drug’s Effectiveness

Researchers have found that using the words “breakthrough” and “promising” in presenting a new drug to the general public often has a dramatic effect on judgment about its effectiveness.... Read more

Lab Technologies

view channel

New Genomic Research Kit Simplifies Exome Studies

An exciting new tool is now available for biotech researchers working in the field of genomic analysis. The human exome is critical to our genetic make-up and is generally accepted as having the greatest influence on how the genetic blueprint is utilized. The exome is defined as all coding exons in the genome and is... Read more


view channel

Sale of Mexican Pharmaceutical Company Expected to Boost Latin American Prescription Drug Market

The sale of a major Mexican pharmaceutical company to an international generic drug corporation is expected to accelerate the growth of the Latin American market for prescription drugs. Teva Pharmaceutical Industries Ltd. (Petah Tikva, Israel) announced that it has entered into definitive agreements to buy Representaciones... Read more


17 Oct 2015 - 21 Oct 2015
25 Oct 2015 - 29 Oct 2015
16 Nov 2015 - 19 Nov 2015
Copyright © 2000-2015 Globetech Media. All rights reserved.