Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis

Liu, Xiao; Li, Junjian; Cadilha, Bruno L.; Markota, Anamarija; Voigt, Cornelia; Huang, Zhe; Lin, Peter Ping; Wang, Daisy D.; Dai, Juncheng; Kranz, Gisela; Krandick, Anna; Libl, Darko; Zitzelsberger, Horst; Zagorski, Isabella; Braselmann, Herbert; Pan, Min; Zhu, Sibo; Huang, Yuanchi; Niedermeyer, Sebastian; Reichel, Christoph; Uhl, Bernd; Briukhovetska, Daria; Suárez, Javier; Kobold, Sebastian; Gires, Olivier; Wang, Hongxia

doi:10.1126/sciadv.aav4275

Cited by 157 publications

(160 citation statements)

References 40 publications

(99 reference statements)

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“…Heterogeneity in epithelial and mesenchymal markers among breast cancer CTCs was reported in many studies [58,[60][61][62][63][64][65]. Moreover, it was reported, that the distribution of these markers in CTCs may be changing during disease progression and treatment [65].…”

Section: Emt Status In Ctcs and Its Prognostic Valuementioning

confidence: 96%

“…Despite many studies, it is unclear which of those two distinct phenotypes may be prognostic for treatment response, PFS and OS. Some research show that mesenchymal phenotype is associated with poor outcome and shorter PFS [58,[65][66][67], but other studies suggest that prognostic value is rather associated with the epithelial phenotype [40,62]. Interestingly, the presence of mesenchymal CTCs was described a predictive factor, regardless of breast cancer subtype [58].…”

Section: Emt Status In Ctcs and Its Prognostic Valuementioning

confidence: 99%

“…It seems that the hybrid phenotype may be the most predictive. Co-expression of E and M markers in CTCs is associated with cancer progression, metastasis and shorter PFS [60][61][62][63]. The E/M population was enriched post-chemotherapy, which corresponded with the lack of response to treatment.…”

Section: Emt Status In Ctcs and Its Prognostic Valuementioning

confidence: 99%

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Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

Fabisiewicz

Szostakowska-Rodzoś

Żaczek

et al. 2020

IJMS

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Breast cancer metastasis is the leading cause of cancer deaths in women and is difficult to combat due to the long periods in which disseminated cells retain a potential to be re-activated and start the relapse. Assessing the number and molecular profile of circulating tumor cells (CTCs) in breast cancer patients, especially in early breast cancer, should help in identifying the possibility of relapse in time for therapeutic intervention to prevent or delay recurrence. While metastatic breast cancer is considered incurable, molecular analysis of CTCs still have a potential to define particular susceptibilities of the cells representing the current tumor burden, which may differ considerably from the cells of the primary tumor, and offer more tailored therapy to the patients. In this review we inspect the routes to metastasis and how they can be linked to specific features of CTCs, how CTC analysis may be used in therapy, and what is the current status of the research and efforts to include CTC analysis in clinical practice.There are two main hypotheses describing cancer dissemination: linear progression, according to which, metastatic potential is gained gradually, and the whole process proceeds in steps and needs time, and parallel progression, according to which dissemination takes place early on, even before clinical manifestation of the tumor [6,7] (Figure 1). In the linear progression model, the evolving primary tumor gives rise to metastases due to increasingly aggressive and invasive phenotypes of the subclones of tumor cells. This model is in agreement with the postulated role of the epithelial-to-mesenchymal transition (EMT) in cancer and assumes active degradation of the stroma and migration into blood vessels by the motile, invasive single cells that broke loose from the epithelial monolayer. In contrast to that, parallel progression postulates intravasation by passive shedding, which may take place shortly after the angiogenic switch, occurring during the early, pre-invasive stage of tumor development [8,9].

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Section: Emt Status In Ctcs and Its Prognostic Valuementioning

confidence: 96%

Section: Emt Status In Ctcs and Its Prognostic Valuementioning

confidence: 99%

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Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

Fabisiewicz

Szostakowska-Rodzoś

Żaczek

et al. 2020

IJMS

View full text Add to dashboard Cite

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“…Aneuploidy-induced cell state transitions may be a novel cause of the strong correlation between aneuploidy and death from cancer. Additionally, recent evidence has underscored the importance of phenotypic plasticity in the metastatic cascade and has suggested that an EMT is neither a necessary nor an irreversible step in cancer cell dissemination (Chen et al 2019;Padmanaban et al 2019;Zheng et al 2015;Fischer et al 2015;Liu et al 2019). Instead, cancer cells can lose certain epithelial characteristics to promote migration out of the primary tumor site and into circulation, but they can re-establish them (through a mesenchymal-epithelial transition) in order to colonize a distant location (Dongre and Weinberg 2019).…”

Section: Discussionmentioning

confidence: 99%

Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer

Vasudevan

Baruah

Smith

et al. 2019

Preprint

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Most human tumors display chromosome-scale copy number alterations, and high levels of aneuploidy are frequently associated with advanced disease and poor patient prognosis. To examine the relationship between aneuploidy and cancer progression, we generated and analyzed a series of congenic human cell lines that harbor single extra chromosomes. We find that different aneuploidies can have distinct effects on invasive behavior: across 13 different cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, chromosomal instability, which can lead to the development of aneuploidy, uniformly suppressed cellular invasion. By analyzing genomic copy number and survival data from 10,133 cancer patients, we demonstrate that specific aneuploidies are associated with distinct clinical outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis.Thus, aneuploidy is not a uniform driver of malignancy, and different chromosome copy number changes can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, underscoring how genomic plasticity can engender phenotypic plasticity and lead to the acquisition of enhanced metastatic properties.

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“…With continuous improvement in 5 CTC detection methods, CTC clusters were identified. Evidence has shown that CTCs in the clusters exhibit epithelial/mesenchymal hybrid (partial EMT) phenotype which allows them to move collectively (8). Collective movement makes these cancer cells to be more apoptosis-resistant and more capable of avoiding immune surveillance and colonizing distant organs.…”

Section: Introductionmentioning

confidence: 99%

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

Chang

Chen

Tsai

et al. 2019

Preprint

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AbstractMetastasis is the major cause of cancer death. Metastatic cancer cells that have intravasated into the circulatory system and formed clusters of circulating tumor cells (CTCs) are particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and CTC clustering remain elusive. We found that high expression of Desmoglein2 (DSG2), a cell adhesion molecule involved in desmosome mediated intercellular adhesion, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process as downregulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress allowed CTCs to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis.Significant StatementDuring metastasis, a hypoxic microenvironment is a major force driving primary tumor cells to disseminate into the circulatory system. The majority of these circulating tumor cells (CTCs) cannot survive when traveling alone. However, collective movement as CTC clusters enables them to avoid immune surveillance and increases the probability that they will successfully metastasize to distal organs. Dynamic down regulation of DSG2 in hypoxic tumor tissue and reactivation of expression in CTCs allowed high rates of tumor cell dissemination, CTC cluster formation and metastasis that are characteristics of the most aggressive breast cancers. The findings highlight both the potential, and potential pitfalls, of using DSG2 as a therapeutic target.

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Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis

Cited by 157 publications

References 40 publications

Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

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