PDGFRα+ Cells in Embryonic Stem Cell Cultures Represent the In Vitro Equivalent of the Pre-implantation Primitive Endoderm Precursors

Nigro, Antonio Lo; Jaime-Soguero, Anchel de; Khoueiry, Rita; Cho, Dong Seong; Ferlazzo, Giorgia Maria; Perini, Ilaria; Escalona, Vanesa Abon; Aranguren, Xabier L.; Lopes, Susana M. Chuva de Sousa; Koh, Kian Peng; Conaldi, Pier Giulio; Hu, Wei Shou; Zwijsen, An; Lluı́s, Frederic; Verfaillie, Catherine M.

doi:10.1016/j.stemcr.2016.12.010

Cited by 31 publications

(45 citation statements)

References 45 publications

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“…In prostate cancer samples, the methylation levels in the ITGA2 promotes were signi cantly decreased compared to normal tissues. ITGA6 was a hypoxia-responsive gene, which enhanced cancer stem cell activity and metastatic phenotypes in breast cancers [26]. These reports together with our nding showed FAM64A could serve as a novel biomarker for PCa and will be helpful to understand the underlying FAM64A -related molecular mechanisms in the progression of PCa.…”

Section: Discussionsupporting

confidence: 57%

FAM64A Promotes Prostate Cancer Growth In Vivo and In Vitro

Cui

et al. 2020

Preprint

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Background Prostate cancer (PCa) is the most common type of human cancer in males. However, the mechanisms underlying PCa tumorigenesis remained unclear.Methods The present study evaluated the expression levels of FAM64A in PCa by using 5 public datasets, including GSE8511, GSE45016, GSE55945, GSE38241 and GSE17951. Then, in vivo and in vitro assays were conducted to detect the biological functions of FAM64A in PCa. Microarray and bioinformatic analysis were carried out to detect the downstream targets and pathways regulated by FAM64A.Results In this study, we for first time demonstrate FAM64A as a biomarker for PCa. FAM64A was found to be overexpressed in PCa compared to normal samples. Higher FAM64A expression were found in Gleason score (GS) ≥ 8 PCa compared to GS < 8 PCa samples, in N1 staging compared to N1 staging PCa samples, and T3/4 staging compared to T1 staging PCa. Moreover, higher FAM64A expression was correlated to shorter survival time in PCa. Knockdown of FAM64A significantly suppressed PCa cell proliferation and colony formation, however, induced PCa apoptosis in vivo and in vitro. Bioinformatics analysis combined with microarray analysis revealed FAM64A played crucial roles in regulating multiple cancer related pathways, including cell-matrix adhesion and cAMP signaling pathway. Conclusions These results showed FAM64A could serve as a novel biomarker for PCa and will be helpful to understand the underlying FAM64A -related molecular mechanisms in the progression of PCa.

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Section: Discussionsupporting

confidence: 57%

FAM64A Promotes Prostate Cancer Growth In Vivo and In Vitro

Cui

et al. 2020

Preprint

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“…It is becoming increasingly apparent that many other cellular processes have multiple intermediate states instead of just one binary or continuous process. For example, stem cell differentiation consists of many intermediate states [53–55]. Thus, it will be exciting to analyze one biological process in different perspectives, including statistical mechanics, mathematical modeling, and single-cell analysis.…”

Section: Discussionmentioning

confidence: 99%

A Plausible Accelerating Function of Intermediate States in Cancer Metastasis

Goetz

Melendez-Alvarez

Chen

et al. 2019

Preprint

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Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers accelerates the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis. KeywordsCancer cell plasticity, partial EMT, microstate, macrostate, intermediate state, Markov 1 process, stabilized state. 2 Introduction 3 Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process in which 4 polarized epithelial cells lose various cell-cell junctions and adhesion and gain migratory 5 and invasive properties to become mesenchymal cells [1, 2]. EMT is very important in 6 embryonic development, tumorigenesis, metastasis, tumour stemness, and therapy 7 resistance [3, 4]. Remarkably, EMT is not a binary process but proceeds with multiple 8 partial intermediate states, collectively known as partial or hybrid EMT states [3, 5-11].9The partial EMT state retains some characteristics of epithelium but also shows 10 features of mesenchymal cells [12][13][14]. One partial EMT state was predicted through 11 mathematical modeling of the EMT core regulatory network and was verified with 12 quantitative experiments by our previous works [5, 6]. Thereafter, many different partial 13 EMT states were proposed [8, 9,[15][16][17]. More and more experimental data shows a 14 different number of partial EMT states in various cancer cell lines [18-23]. Recently, 15 r 1, 2019 1/26 several partial EMT phenotypes were found during cancer metastasis in vivo in a skin 16 cancer mouse model [24, 25] and prostate cancer [26]. While many partial EMT states 17 have been found, their functions are still not fully understood during cancer 18 metastasis [4, 27-29]. 19 Currently, the function of partial EMT states has being studied in the context of 20 coupling with other cellular processes. For example, acquisition of stem-like properties 21 dictates its coupling with cancer stemness [11, 30-34], circulating tumor cells 22 (CTCs) [35, 36], and drug resistance [37]. Thus, the partial EMT cells hold the highest 23 metastatic potential. As well, partial EMT, instead of full EMT, is found to be critical 24 for renal fibrosis [38-40]. There are many potential couplings of partial EMT and other...

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“…(a) nEnd cells and pXEN cells are mixes or equilibria of less mature with VE or PE cells, respectively. Such “mosaic” model appeals as it mirrors the well‐studied ES cell lines, which are seen as epiblast‐dominated mixes or equilibria of closely related pre‐implantation cell types (e.g., Lo Nigro et al, ; Canham et al, ). (b) Individual pXEN and nEnd cells show hybrid phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…The second group includes rat and mouse blastocyst‐derived “primitive XEN (pXEN)” (Debeb et al, ; Zhong et al, ) and mouse ES cell‐derived “naïve extraembryonic endoderm progenitor (nEnd)” (Anderson et al, ) cell lines. In addition, numerous PrE‐related cells were isolated from ES cell cultures but not grown as lines (e.g., Canham, Sharov, Ko, & Brickman, ; Lo Nigro et al, ); from this group, we selected the “PrE‐primed ES cells” (Lo Nigro et al, ). The second group and PrE‐like ES cells are distinct from the “XEN group” as follows: They require the cytokine LIF (see also Supporting Information Table S1), express Pou5f1, can directly contribute to the VE and appeared closer to the blastocyst in transcriptome comparisons (Anderson et al, ; Debeb et al, ; Lo Nigro et al, ; Zhong et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, numerous PrE‐related cells were isolated from ES cell cultures but not grown as lines (e.g., Canham, Sharov, Ko, & Brickman, ; Lo Nigro et al, ); from this group, we selected the “PrE‐primed ES cells” (Lo Nigro et al, ). The second group and PrE‐like ES cells are distinct from the “XEN group” as follows: They require the cytokine LIF (see also Supporting Information Table S1), express Pou5f1, can directly contribute to the VE and appeared closer to the blastocyst in transcriptome comparisons (Anderson et al, ; Debeb et al, ; Lo Nigro et al, ; Zhong et al, ). nEnd and pXEN cells were easily converted into XEN‐like cells, but not vice versa (Anderson et al, ; Zhong et al, ), again arguing that XEN cells are more differentiated.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome analysis shows ambiguous phenotypes of murine primitive endoderm‐related stem cell lines

Zhong

Binas

2019

Genes to Cells

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Primitive endoderm (PrE)‐related cell lines (XEN, pXEN and nEnd cells) show key features of the PrE. By transcriptome analysis, we show: (a) Compared to embryonic stem cells, PrE‐related cell lines are less in vivo like, although early nEnd cells are most similar to the PrE. (b) These cell lines show post‐PrE features of parietal (XEN and pXEN cells) or visceral (nEnd cells) endoderm, likely driven by Tgf‐β and Wnt/Activin signaling, respectively. (c) pXEN and nEnd cell lines additionally show pre‐PrE features. Hence, neither pXEN nor nEnd cell cultures represent a distinct in vivo entity. Rather, their properties are compatible with mixed and hybrid phenotypes. Our findings indicate that pre‐PrE, PrE and early post‐PrE phenotypes result from different niches, which need to be better understood to derive cell lines that distinctly represent the early stages of the extraembryonic endoderm.

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PDGFRα+ Cells in Embryonic Stem Cell Cultures Represent the In Vitro Equivalent of the Pre-implantation Primitive Endoderm Precursors

Cited by 31 publications

References 45 publications

FAM64A Promotes Prostate Cancer Growth In Vivo and In Vitro

FAM64A Promotes Prostate Cancer Growth In Vivo and In Vitro

A Plausible Accelerating Function of Intermediate States in Cancer Metastasis

Transcriptome analysis shows ambiguous phenotypes of murine primitive endoderm‐related stem cell lines

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