Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer

Abstract

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2–driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2–centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2

“…4C, Supplementary Table 7). The difference in our observations compared to Guerra et al [ 20 ] who found an increase of TROP2 in metastatic lesions could be explained by the usage of different antibodies, the inclusion of a high number of rectal cancer, and the scoring approach. Otherwise, when analyzing the in silico dataset GSE41258 comparing the gene expression of TROP2 and ATF2 in non-paired 182 primary tumors and 47 liver metastasis, both markers showed a probe-dependent high variance in gene expression scores in both cohorts (Supplementary Fig.…”

“…7F). Finally, these findings support previous reports from literature showing a pro-migratory role for TROP2 [ 20 , 23 , 24 ].…”

“…Correspondingly, in vivo, TROP2-overexpressing xenografts grew as loosely packed tumors and a disturbed pattern of cellular contacts was further reflected by the deregulation of the adhesion molecules MCAM and ICAM in a NanoString analysis. Interestingly, the higher migration and invasiveness in TROP2-overexpressing ATF2-KO cell lines were not associated with robust EMT signs as already shown in three different tumor entities by Remsik et al for breast and prostate cancer [ 36 ], and Guerra et al for colorectal cancer [ 20 ]. In the NanoString analysis, EMT markers, such as CD44 and TWIST1 , were even down-regulated, and ZEB1 , SNAI2 , and E-Cadherin levels were unchanged, supporting the findings of Guerra et al who described an EMT-less invasion in their TROP2-overexpressing metastatic cells [ 20 ].…”

“…Interestingly, the higher migration and invasiveness in TROP2-overexpressing ATF2-KO cell lines were not associated with robust EMT signs as already shown in three different tumor entities by Remsik et al for breast and prostate cancer [ 36 ], and Guerra et al for colorectal cancer [ 20 ]. In the NanoString analysis, EMT markers, such as CD44 and TWIST1 , were even down-regulated, and ZEB1 , SNAI2 , and E-Cadherin levels were unchanged, supporting the findings of Guerra et al who described an EMT-less invasion in their TROP2-overexpressing metastatic cells [ 20 ]. Thus, we suggest that ATF2 loss seems to reinforce the epithelial differentiation.…”

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

“…In cancer cells, Trop-2 overexpression stimulates growth and metastatic potential by promoting cell proliferation and migration. This protein is also involved in the epithelial-to-mesenchymal transition (EMT) since it determines E-cadherin down-regulation and vimentin expression, resulting in cell migration and stem cell-like properties [ 5 , 6 , 7 , 8 ]. Additionally, Trop-2 enhances cellular motility and invasion through the up-regulation of integrin-dependent signaling [ 3 , 4 ].…”