Article Alert: Targeting the MMP-2/TYRO3/BRD3 Axis Ameliorates Colorectal Cancer Malignancy

Receptor tyrosine kinases (RTKs) are well known to drive cancer progression and metastasis when mutated or aberrantly expressed (1). However, the suboptimal efficacy of small-molecule inhibitors that target the downstream signaling events initiated by oncogenic RTKs indicates that noncanonical mechanisms are also contributing to RTK-dependent malignant progression.

An exciting study by Hsu et al. identifies how an RTK operates through a noncanonical pathway to promote colorectal cancer (CRC) malignancy (2). The authors examined the role of TYRO3 (a TAM (TYRO3, AXL, and MER) family RTK) in CRC progression using a number of in vitro techniques, human CRC tissue samples, organoids, and mouse models. They found that matrix metalloproteinase-2 (MMP-2) proteolytically cleaves TYRO3, which leads to its nuclear translocation. Nuclear TYRO3 then phosphorylates bromodomain-containing protein 3 (BRD3), an acetyl-lysine reader and epigenetic regulator, that binds genes related to cell growth, epithelial-mesenchymal transition (EMT), and metastasis. The researchers show that inhibition of MMP-2 or BRD3 abrogates the protumor effects of nuclear TYRO3. Thus, the work by Hsu et al. not only describes the MMP-2/TYRO3/BRD3 axis that appears to be crucial for the malignancy of some CRCs, but also reinforces the idea that targeting noncanonical pathways may lead to better therapies for oncogenic RTK-related malignancies.

GeneTex offers a very extensive catalog of antibody reagents for cancer biology research, including the MMP2 antibody (GTX104577), Caspase 3 antibody (GTX110543), SLUG antibody (GTX128796), Lamin A + C antibody (GTX101127), and ZEB1 antibody (GTX105278) cited in the Hsu et al. paper. For more information, please see the product data images below and visit www.genetex.com.