MUC1 Drives c-Met–Dependent Migration and Scattering

Abstract

The transmembrane mucin MUC1 is overexpressed in most ductal carcinomas, and its overexpression is frequently associated with metastatic progression. MUC1 can drive tumor initiation and progression via interactions with many oncogenic partners, including β-catenin, the epidermal growth factor receptor (EGFR) and Src. The decoy peptide PMIP (Protein transduction domain MUC1 Inhibitory Peptide) has been shown to inhibit the tumor promoting activities of MUC1 in breast and lung cancer, including cell growth and invasion, and its usage suppresses metastatic progression in mouse models of breast cancer. To further characterize the reduced metastasis observed upon PMIP treatment, we performed motility assays and observed that PMIP inhibits cell motility of breast cancer cells. To determine the mechanism by which PMIP inhibits motility, we evaluated changes in global gene transcription upon PMIP treatment, and identified a number of genes with altered expression in response to PMIP. Among these genes is the metastatic mediator, c-Met, a transmembrane tyrosine kinase that can promote cell scattering, migration and invasion. To further investigate the role of c-Met in MUC1-dependent metastatic events, we evaluated the effects of MUC1 expression and EGFR activation on breast cancer cell scattering, branching and migration. We found that MUC1 strongly promoted all of these events and this effect was further amplified by EGF treatment. Importantly, the effect of MUC1 and EGF on these phenotypes was dependent upon c-Met activity. Overall, these results indicate that PMIP can block the expression of a key metastatic mediator, further advancing its potential use as a clinical therapeutic.

Design and Optimization of a Series of 1-Sulfonylpyrazolo[4,3-b]pyridines as Selective c-Met Inhibitors

“…11, 12 Abnormal activation of c-Met has been 11 reported in many types of cancers, occurring as a consequence of gene amplification 12 or rearrangement, transcriptional regulation as well as autocrine or paracrine ligand 13 stimulation. [13][14][15][16] Importantly, overexpression of HGF and/or c-Met have been 14 associated with poor prognosis or metastatic progression. In addition, Met 15 amplification is observed in 20% of acquired resistance to EGFR inhibitors.…”

“…In addition, Met 15 amplification is observed in 20% of acquired resistance to EGFR inhibitors. 17 Tumor 16 micro-environment elicits innate resistance to BRAF inhibitors via HGF secretion. 18 …”

“…Figure 1 13 listed some type I inhibitors, including a marketed drug crizotinib (1) 24 , and two phase 14 II clinical trial compounds (2,3) 25,26 . Implied by the unique U-shaped binding mode, 15 type I inhibitors all show good selectivity for c-Met, which is thought to give less side 16 effects in cancer treatment. Type II c-Met inhibitors usually adopt an extended 17 conformation, starting from the solvent-accessible part to hinge, and further stretching 18 to the deep hydrophobic Ile1145 subpocket near the C-helix region.…”

“…A novel more 14 metabolically stable scaffold was discovered, and further optimization resulted in a 15 series of high potent, selective c-Met inhibitors. Based on the extensive in vivo 16 pharmacology and pharmacokinetics studies, compound 46 was selected as promising 17 candidate and subjected to further development. 18 19 Results and Discussion 20 Inhibitor design and lead identification 21 Sulfonyl-4-azaindoles acting as novel c-Met inhibitors were discovered by Porter et al 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 6 from a high throughput screening campaign.…”

MUC1 and metastatic cancer

“…87 We found that treatment with a competitive MUC1 inhibitor downregulates c-Met in breast cancer cells, and that MUC1 promotes EGFand c-Met-dependent cell motility, scattering and the formation of invasive protrusions. 88 In addition, MUC1 has recently been found to be upregulated in a subset of lung cancers which also have upregulated or constitutively active EGFR and c-Met. 89 In this study, lung cancer cell lines were analyzed for expression of genes associated with tumorigenesis, and MUC1, EGFR and c-Met expression were positively correlated.…”