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Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro.

ABSTRACT: Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an in vitro mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the surrounding extracellular matrix to facilitate invasion. In this study, we examine changes in gene expression in response to tugging on matrix fibers. Interestingly, we find that integrin ?3 expression is downregulated and leads to an increase in cofilin activity, as evidenced by a reduction in its Ser3 phosphorylation levels. As a result, invadopodia lengthen and have increased enzymatic activity, indicating that transient mechanical stimulation promotes the maturation of invadopodia leading to increased levels of cell invasion. Our results are unique in defining an invasive mechanism specific to the invasive process of cancer cells that is triggered by tugging forces in the microenvironment, as opposed to rigidity, compression or stretch forces.

SUBMITTER: Gasparski AN

PROVIDER: S-EPMC6865334 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion <i>in vitro</i>.

Gasparski Alexander N AN Ozarkar Snehal S Beningo Karen A KA

Journal of cell science 20170426 11

Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an <i>in vitro</i> mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the sur ...[more]

PMID: 28446539

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Project description:The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.

Dataset Information

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro.

Publications

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion <i>in vitro</i>.

Similar Datasets

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