DSG2 Is a Functional Cell Surface Marker for Identification and Isolation of Human Pluripotent Stem Cells

Park, Jong Jin; Son, YeonSung; Lee, Na Geum; Lee, Kyung-Min; Lee, Dong Gwang; Song, Jinhoi; Lee, Jaemin; Kim, Seokho; Cho, Min Ji; Jang, Ju Hong; Lee, Jangwook; Park, Jong Gil; Kim, Yeon Gu; Kim, Jang Seong; Lee, Jungwoon; Cho, Yee Sook; Park, Young Jun; Han, Baek Soo; Bae, Kwang‐Hee; Han, Seungmin; Kang, Byunghoon; Haam, Seungjoo; Lee, Sang Chul; Min, Jeong Ki

doi:10.1016/j.stemcr.2018.05.009

Cited by 20 publications

(19 citation statements)

References 38 publications

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“…S6), suggesting that DSG2 may contribute to CTC survival during circulation and may help maintain cancer stemness. Consistent with this notion, DSG2 has recently been identified as a marker for pluripotent stem cells (PSCs) and is critical for PSC self-renewal and reprogramming (37). These observations could partially explain why there was no significant difference or even higher single CTC numbers in mice bearing cancer cells with high overall DSG2 level (shCtrl) compared to mice bearing DSG2-depleted (shDSG2) cancer cells (Fig.…”

Section: Discussionmentioning

confidence: 78%

“…Moreover, CTCs that can survive in the circulatory system and colonize in distant organs are thought to be cancer stem-like cells and are highly correlated with metastasis (47,48). Consistent with this notion, DSG2 has recently been identified as a marker for pluripotent stem cells (PSCs) and is critical for PSC self-renewal and reprogramming (49). How DSG2 may contribute to cancer stemness is another topic of interest for further experiments.…”

Section: Discussionmentioning

confidence: 86%

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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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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 86%

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

Chang

Chen

Tsai

et al. 2019

Preprint

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“…In epithelial cells, adenovirus binding to DSG2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions [ 158 ]. DSG2 also regulates β-catenin-mediated EMT signaling in pluripotent stem cells [ 159 ].…”

Section: Appendixmentioning

confidence: 99%

Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics

Kurakin

Bredesen

2020

Aging

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Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks. Using algorithms for hypothesis independent search and expert-assisted synthesis of heterogeneous data, we attempted to reconcile multimodal clinical profiles of early-stage AD patients and accumulated research data within a parsimonious framework. Results of our analysis suggest that Alzheimer’s may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis. The latter can be caused by various endogenous and exogenous factors, such as chronic inflammatory conditions, infections, vascular dysfunction, head trauma, environmental toxicity, and immune disorders. Whether originating in the brain or on the periphery, chronic stress, toxicity, and inflammation are communicated to the central nervous system (CNS) via humoral and neural routes, preferentially targeting high-centrality regulatory nodes and circuits of the nervous system, and eventually manifesting as a neurodegenerative CNS disease. In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer’s disease.

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“…They also identified two other mAbs that bind to surface proteins on both hESCs and cancer cell lines, though the identities of the antigens were not determined [27]. Independently, Son et al, using conventional hybridoma technology, raised a panel of mAbs against hESC, of which two mAbs were shortlisted and characterized [28,29]. The first mAb, 4-63, was found to bind to the antigen L1 cell adhesion molecule (L1CAM) on undifferentiated PSCs [28].…”

Section: Mabs For Regenerative Cell Therapymentioning

confidence: 99%

“…L1CAM was found to play an important role in self-renewal by activating fibroblast growth factor receptor 1 signaling. The second mAb binds to desmoglein-2 (DSG2) on undifferentiated hESCs, and its surface expression is rapidly downregulated upon differentiation [29]. Their studies further revealed that DSG2 is essential to the self-renewal of PSCs and the acquisition of pluripotency during somatic cell reprogramming by controlling β-catenin/slug-mediated epithelial mesenchymal transition.…”

Section: Mabs For Regenerative Cell Therapymentioning

confidence: 99%

Opportunities for Antibody Discovery Using Human Pluripotent Stem Cells: Conservation of Oncofetal Targets

Tan

Choo

2019

IJMS

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Pluripotent stem cells (PSCs) comprise both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The application of pluripotent stem cells is divided into four main areas, namely: (i) regenerative therapy, (ii) the study and understanding of developmental biology, (iii) drug screening and toxicology and (iv) disease modeling. In this review, we describe a new opportunity for PSCs, the discovery of new biomarkers and generating antibodies against these biomarkers. PSCs are good sources of immunogen for raising monoclonal antibodies (mAbs) because of the conservation of oncofetal antigens between PSCs and cancer cells. Hence mAbs generated using PSCs can potentially be applied in two different fields. First, these mAbs can be used in regenerative cell therapy to characterize the PSCs. In addition, the mAbs can be used to separate or eliminate contaminating or residual undifferentiated PSCs from the differentiated cell product. This step is critical as undifferentiated PSCs can form teratomas in vivo. The mAbs generated against PSCs can also be used in the field of oncology. Here, novel targets can be identified and the mAbs developed as targeted therapy to kill the cancer cells. Conversely, as new and novel oncofetal biomarkers are discovered on PSCs, cancer mAbs that are already approved by the FDA can be repurposed for regenerative medicine, thus expediting the route to the clinics.

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DSG2 Is a Functional Cell Surface Marker for Identification and Isolation of Human Pluripotent Stem Cells

Cited by 20 publications

References 38 publications

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics

Opportunities for Antibody Discovery Using Human Pluripotent Stem Cells: Conservation of Oncofetal Targets

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