The first direct evidence that ‘invadopodia’ play a role in tissue cell invasion in vivo

· TGI - Cancer, TGI - Intestinal Tract


Reported by: Dr. Venkat S. Karra, Ph.D.

The epithelial cells lining the digestive tract are separated from the connective tissue stroma by a thin layer of extracellular matrix called the basement membrane. During cell invasion, as occurs during cancer metastasis, epithelial cells breach the basement membrane and invade the tissue stroma. The proteases used by invasive cells to degrade basement membrane in vitro are localized in specialized plasma membrane protrusions known as invadopodia. It is not known, however, whether invadopodia are required for cell invasion in vivo or what triggers their formation.

Invasion of cancer cells through their basement membrane is an early event during tumor progression and is a histological feature that distinguishes cancers from benign tumors. In vitro models suggest cancer cell invasion requires the formation of invadopodia, actin-rich membrane protrusions that provide a localized source of matrix degrading proteases [1][2]. Invadopodia and structurally related podosomes were first discovered in cells transformed with the Rous Sarcoma Virus oncogenev-SRC (reviewed in [2]). High levels of endogenous SRC are thought to promote invadopodia that form spontaneously in invasive cancer cells or following activation of growth factor signaling pathways[2].

Changes in substrate rigidity were recently shown to alter the number and activity of invadopodia that form spontaneously in invasive breast cancer cells [3],[4], thus providing a potential mechanistic link between invasion and physical signaling. Although invadopodia have been studied extensively in cell culture models, their precise role in cell invasion in vivo has not yet been determined [2].

In previous work, they showed that cell invasion can be modeled in a zebrafish mutant, meltdown (mlt), in which intestinal architecture is disrupted by a mutation in myosin heavy chain 11 (myh11), the gene encoding the principle myosin present in smooth muscle [5].

Now they show the first direct evidence that invadopodia play a role in tissue cell invasion in vivo and identify a novel inducible physical signaling mechanism that can drive the process.

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