Trop-2 plasticity is controlled by epithelial-to-mesenchymal transition

Remšík, Ján; Binó, Lucia; Kahounová, Zuzana; Kharaishvili, Gvantsa; Šimečková, Šárka; Fedr, Radek; Kučírková, Tereza; Lenárt, Sára; Muresan, Ximena Maria; Slabáková, Eva; Knopfová, Lucia; Bouchal, Jan; Král, Milan; Beneš, Petr; Souček, Karel

doi:10.1093/carcin/bgy095

Cited by 24 publications

(28 citation statements)

References 25 publications

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“…Low Trop2 expression associates with poor overall survival, invasion, and poor differentiation in hepatocellular carcinomas [ 88 ], but not in cholangiocarcinomas [ 75 ]. Similarly, our study shows that in lymph-node-positive breast cancer and prostate cancer patients, low expression of TACSTD2 mRNA associates with worse prognosis [ 137 ].…”

Section: Trop2 In Cancermentioning

confidence: 79%

“…Other miRNAs that target Trop2 were also identified in head-and-neck carcinoma [ 134 ] and urothelial bladder cancer [ 135 ]. Furthermore, we and others showed that Trop2 expression is regulated by methylation of TACSTD2 gene promoter in various cancer cells [ 73 , 75 , 88 , 136 , 137 ]. Importantly, Lin et al found hypermethylation of TACSTD2 gene promoter in lung adenocarcinoma tissues and cell lines explaining low expression of Trop2 in this type of cancer [ 73 ].…”

Section: Trop2 In Cancermentioning

confidence: 99%

“…Our recent study found that the membrane expression of Trop2 positively correlates with E-cadherin expression and negatively with the mesenchymal gene signature in a wide panel of human and murine breast and prostate cancer cell lines, as well as human tumors [ 137 ]. Our findings suggest that in breast and prostate cancers, the surface Trop2 expression associates with the epithelial phenotype.…”

Section: Trop2 In Cancermentioning

confidence: 99%

“…Our findings suggest that in breast and prostate cancers, the surface Trop2 expression associates with the epithelial phenotype. Furthermore, we have shown that the Trop2 expression is suppressed either epigenetically through the DNA hypermethylation or EMT transcription factors, i.e., ZEB1 during EMT [ 137 ]. Similarly, the protein level of E-cadherin is significantly decreased in the absence of mTrop2 (murine Trop2) in immortalized murine keratinocytes [ 35 ].…”

Section: Trop2 In Cancermentioning

confidence: 99%

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Trop2: Jack of All Trades, Master of None

Lenárt

Šmarda

et al. 2020

Cancers

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Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug–antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.

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Section: Trop2 In Cancermentioning

confidence: 79%

Section: Trop2 In Cancermentioning

confidence: 99%

Section: Trop2 In Cancermentioning

confidence: 99%

Section: Trop2 In Cancermentioning

confidence: 99%

See 2 more Smart Citations

Trop2: Jack of All Trades, Master of None

Lenárt

Šmarda

et al. 2020

Cancers

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“…The epithelial and mesenchymal sublines were established from sorted single cell clones derived from Trop-2 positive or Trop-2 negative populations, as shown in Remsik et al . 25 . PC-3 cells were cultivated in Ham’s F12 media (TFS) with 10% of FBS, penicillin and streptomycin.…”

Section: Methodsmentioning

confidence: 99%

High Skp2 expression is associated with a mesenchymal phenotype and increased tumorigenic potential of prostate cancer cells

Šimečková

Kahounová

Fedr

et al. 2019

Sci Rep

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Skp2 is a crucial component of SCF Skp2 E3 ubiquitin ligase and is often overexpressed in various types of cancer, including prostate cancer (PCa). The epithelial-to-mesenchymal transition (EMT) is involved in PCa progression. The acquisition of a mesenchymal phenotype that results in a cancer stem cell (CSC) phenotype in PCa was described. Therefore, we aimed to investigate the expression and localization of Skp2 in clinical samples from patients with PCa, the association of Skp2 with EMT status, and the role of Skp2 in prostate CSC. We found that nuclear expression of Skp2 was increased in patients with PCa compared to those with benign hyperplasia, and correlated with high Gleason score in PCa patients. Increased Skp2 expression was observed in PCa cell lines with mesenchymal and CSC-like phenotype compared to their epithelial counterparts. Conversely, the CSC-like phenotype was diminished in cells in which SKP2 expression was silenced. Furthermore, we observed that Skp2 downregulation led to the decrease in subpopulation of CD44 + CD24 − cancer stem-like cells. Finally, we showed that high expression levels of both CD24 and CD44 were associated with favorable recurrence-free survival for PCa patients. This study uncovered the Skp2-mediated CSC-like phenotype with oncogenic functions in PCa.

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

Huebner

Erlenbach-Wuensch

Procházka

et al. 2022

Cell. Mol. Life Sci.

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In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2KO/TROP2high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2low/TROP2high expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.

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Trop-2 plasticity is controlled by epithelial-to-mesenchymal transition

Cited by 24 publications

References 25 publications

Trop2: Jack of All Trades, Master of None

Trop2: Jack of All Trades, Master of None

High Skp2 expression is associated with a mesenchymal phenotype and increased tumorigenic potential of prostate cancer cells

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

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