Invadopodia, a Kingdom of Non-Receptor Tyrosine Kinases

Abstract

Non-receptor tyrosine kinases (NRTKs) are crucial mediators of intracellular signaling and control a wide variety of processes such as cell division, morphogenesis, and motility. Aberrant NRTK-mediated tyrosine phosphorylation has been linked to various human disorders and diseases, among them cancer metastasis, to which no treatment presently exists. Invasive cancer cells leaving the primary tumor use invadopodia, feet-like structures which facilitate extracellular matrix (ECM) degradation and intravasation, to escape the primary tumor and disseminate into distant tissues and organs during metastasis. A major challenge in metastasis research is to elucidate the molecular mechanisms and signaling pathways underlying invadopodia regulation, as the general belief is that targeting these structures can potentially lead to the eradication of cancer metastasis. Non-receptor tyrosine kinases (NRTKs) play a central role in regulating invadopodia formation and function, but how they coordinate the signaling leading to these processes was not clear until recently. Here, we describe the major NRTKs that rule invadopodia and how they work in concert while keeping an accurate hierarchy to control tumor cell invasiveness and dissemination.

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

“…During cancer cell invasion, cells switch back and forth between periods of integrin-mediated migration and invadosome-mediated matrix degradation and passage [ 379 , 380 ]. Several non-receptor tyrosine kinases (NRTKs) jointly regulate invadopodia formation and function and, thus, control the balance between local tumor growth on the one hand and invasiveness and spread of tumor cells on the other hand [ 381 ]. FAK counteracts the formation of invadopodia by withdrawing Src from invadopodia and recruiting it into focal adhesions [ 382 ].…”

“…Inhibition of NRTKs in the PTK2B-Src-ABL2-cortactin cascade, in particular of ABL2, effectively inhibits the invadopodia-mediated invasiveness and metastasis of human breast cancer cells in a mouse tumor model [ 493 ]. The interaction between PTK2B and FAK in controlling the formation and function of invadopodia suggests the inhibition of both kinases in order to curb metastasis [ 381 ].…”

Identification of Inhibitors and Drug Targets for Human Adenovirus Infections

“…Based on the kinase domain sequence, these 58 receptor tyrosine kinases can be grouped into 20 subfamilies, including EGFR, FGFR, PDGFR, and VEGFR. The 32 non-receptor tyrosine kinases fall into ten subfamilies, including SRC and SYK [ 22 , 23 , 24 ].…”

Text-Mining Approach to Identify Hub Genes of Cancer Metastasis and Potential Drug Repurposing to Target Them

“…Additionally, the gene/process association heatmap (Supplementary Figure S1) portrayed a set of genes, clustered with invadopodia and podosome but not with other processes, suggesting their role specific to invadopodia and podosome. For instance, genes such as CTTN, NCK1, SH3PXD2A, CDC42, ADAM12, SRC, RHO, PTK2, PTK2B, PXN, ADAM12, etc., are known regulators of invadopodia and podosome formation [48,49,52]. Even though genes such as SRC, RHO, PTK2, and CDC42 are also involved in other processes [53][54][55], genes specific to invadopodia and podosome formation still possess importance to be targeted as a promising therapeutic target due to their relevance to be involved in metastasis-related processes.…”