scholarly journals Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice

2016 ◽  
Vol 213 (10) ◽  
pp. 2019-2037 ◽  
Author(s):  
Pengpeng Bi ◽  
Feng Yue ◽  
Anju Karki ◽  
Beatriz Castro ◽  
Sara E. Wirbisky ◽  
...  
Keyword(s):  
Gene Expression Signature ◽  
Lineage Tracing ◽  
Metabolic Dysfunction ◽  
Cellular Origin ◽  
Complete Penetrance ◽  
Pten Deletion ◽  
Anatomical Localization ◽  
Tumorigenic Transformation ◽  
Tissue Cancer ◽  
Notch Activation

Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction. Although concomitant Pten deletion normalizes the glucose metabolism of Ad/N1ICD mice, it dramatically accelerates the LPS prognosis and malignancy. Transcriptomes and lipidomics analyses indicate that Notch activation suppresses lipid metabolism pathways that supply ligands to Pparγ, the master regulator of adipocyte homeostasis. Accordingly, synthetic Pparγ ligand supplementation induces redifferentiation of Ad/N1ICD adipocytes and tumor cells, and prevents LPS development in Ad/N1ICD mice. Importantly, the Notch target HES1 is abundantly expressed in human LPS, and Notch inhibition suppresses the growth of human dedifferentiated LPS xenografts. Collectively, ectopic Notch activation is sufficient to induce dedifferentiation and tumorigenic transformation of mature adipocytes in mouse.

Abstract P011: Endothelial Differentiation and Lineage Tracing in Adipocyte-Derived Multipotent Cells

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Medet Jumabay ◽  
Raushan Abdmaulen ◽  
Yucheng Yao ◽  
Kristina Bostrom
Keyword(s):  
Stem Cell ◽  
Lineage Tracing ◽  
Collagen Gels ◽  
Cellular Origin ◽  
Differentiated Cells ◽  
Stem Cell Source ◽  
Cardiovascular Regeneration ◽  
Morphogenetic Protein ◽  
Dfat Cells

We previously showed that so-called de-differentiated fat (DFAT) cells, which are derived from mature white adipocytes, spontaneously differentiate into beating cardiomyocytes. Our aim in this study was to investigate if DFAT cells also differentiate into endothelial cells (ECs) in vitro, and to further examine the cellular origin of DFAT cells as well as adipose stromal cells (ASCs) using lineage tracing. First, we examined DFAT and ASCs prepared from aP2-Cre+/+;LacZ ROSA(R26R)+/+ double transgenic mice, which express LacZ under the aP2 promoter. The results revealed that 99.9% of DFAT cells and 45% of the ASCs stained positive for LacZ, supporting that the DFAT cells and part of the ASCs are of adipocytic origin. Second, we allowed newly isolated DFAT cells to spontaneously undergo EC differentiation, which was monitored by expression of EC lineage markers as determined by real-time PCR, immunofluorescence, and FACS. Expression of the EC markers CD31 and VE-cadherin increased progressively during 2 weeks in culture, the percentage of CD31(+) cells increased from 0.0% to 8.3%, and the cells formed multi-cellular tube structures when placed in Matrigel™/Collagen gels. The data supported that a fraction of the DFAT cells differentiate into ECs. Furthermore, the EC differentiation could be enhanced in DFAT cells by treatment with bone morphogenetic protein (BMP)-4 and BMP-9. In addition to EC differentiation, the DFAT cells also expressed markers of other cardiovascular lineages including smooth muscle cells and pericytes. The multipotency of DFAT cells suggests that cellular de-differentiation might be a way for differentiated cells to regain stem cell-like properties. Thus, white mature adipocytes maybe a new stem cell source for cardiovascular regeneration.

scholarly journals SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27 null mice

2020 ◽  
Author(s):  
Veronica Moncho-Amor ◽  
Probir Chakravarty ◽  
Christophe Galichet ◽  
Ander Matheu ◽  
Robin Lovell-Badge ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Regulatory Region ◽  
Lineage Tracing ◽  
Intermediate Lobe ◽  
Loss Of Function ◽  
Cellular Origin ◽  
Differentiated Cells ◽  
Pituitary Tumorigenesis ◽  
Cellular Context ◽  
Pituitary Intermediate Lobe

AbstractLoss of P27 predominantly results in development of murine pituitary intermediate lobe (IL) tumours. We previously showed that the pleiotropic protein P27 can drive repression of the transcription factor Sox2. This interaction plays an important role during development of p27-/- IL tumours because loss of one copy of Sox2 diminishes tumorigenesis. Here, we have explored the cellular origin and mechanisms underlying melanotroph tumorigenesis in p27-/- IL. We show that IL hyperplasia is associated with reduced cellular differentiation, while levels of SOX2 increase in both stem cells (SC) and melanotrophs. Using loss-of-function and lineage tracing approaches, we demonstrate that SOX2 is required cell-autonomously in p27-/- melanotrophs and SCs for tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), which is the target of P27 repressive action. Single cell transcriptomic analysis reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for p27-/- tumorigenesis. Our data highlight different roles of SOX2 following loss of p27, according to the cellular context. Furthermore, we uncover a tumor-promoting function for SCs, which is SOX2-dependant. In conclusion, our results imply that targeting SCs, in addition to tumour cells themselves, may represent an efficient anti-tumoral strategy in certain contexts.

scholarly journals Repopulating Kupffer Cells Originate Directly from Hematopoietic Stem Cells

2021 ◽  
Author(s):  
Xu Fan ◽  
Pei Lu ◽  
Xianghua Cui ◽  
Peng Wu ◽  
Weiran Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Kupffer Cells ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Fate Mapping ◽  
Monocytic Cell ◽  
Hematopoietic Stem ◽  
Cellular Origin

Abstract Kupffer cells (KCs) originate from yolk sac progenitors before birth, but the origin of repopulating KCs in adult remains unclear. In current study, we firstly traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate mapping mouse models, respectively, and found no evidences that repopulating KCs originate from preexisting KCs or MOs. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC depletion in mice, and found that in response to KC depletion, hematopoietic stem cells (HSCs) proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Finally, we traced the fate of HSCs in a HSC-specific fate-mapping mouse model, in context of chronic liver inflammation induced by repeated carbon tetrachloride treatment, and confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided in vivo fate-mapping evidences that repopulating KCs originate directly from hematopoietic stem cells, which present a completely novel understanding of the cellular origin of repopulating Kupffer Cells and shedding light on the divergent roles of KCs in liver homeostasis and diseases.

scholarly journals Breast Cancer Stem Cells: Biomarkers, Identification and Isolation Methods, Regulating Mechanisms, Cellular Origin, and Beyond

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3765
Author(s):  
Xiaoli Zhang ◽  
Kimerly Powell ◽  
Lang Li
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Current Knowledge ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Breast Cancer Stem Cells ◽  
Full Spectrum ◽  
Cellular Origin ◽  
Treatment Responses

Despite recent advances in diagnosis and treatment, breast cancer (BC) is still a major cause of cancer-related mortality in women. Breast cancer stem cells (BCSCs) are a small but significant subpopulation of heterogeneous breast cancer cells demonstrating strong self-renewal and proliferation properties. Accumulating evidence has proved that BCSCs are the driving force behind BC tumor initiation, progression, metastasis, drug resistance, and recurrence. As a heterogeneous disease, BC contains a full spectrum of different BC subtypes, and different subtypes of BC further exhibit distinct subtypes and proportions of BCSCs, which correspond to different treatment responses and disease-specific outcomes. This review summarized the current knowledge of BCSC biomarkers and their clinical relevance, the methods for the identification and isolation of BCSCs, and the mechanisms regulating BCSCs. We also discussed the cellular origin of BCSCs and the current advances in single-cell lineage tracing and transcriptomics and their potential in identifying the origin and lineage development of BCSCs.

scholarly journals Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

2020 ◽  
Author(s):  
Karin D. Prummel ◽  
Helena L. Crowell ◽  
Susan Nieuwenhuize ◽  
Eline C. Brombacher ◽  
Stephan Daetwyler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Single Cell Analysis ◽  
De Novo ◽  
Primordial Germ Cells ◽  
Gene Expression Signature ◽  
Time Lapse ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Lateral Plate

AbstractThe mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.

scholarly journals Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

2017 ◽  
Vol 114 (19) ◽  
pp. E3806-E3815 ◽  
Author(s):  
Hayato Nakagawa ◽  
Nobumi Suzuki ◽  
Yoshihiro Hirata ◽  
Yohko Hikiba ◽  
Yoku Hayakawa ◽  
...  
Keyword(s):  
Bile Duct ◽  
Mouse Model ◽  
Time Course ◽  
Extrahepatic Bile Duct ◽  
Genetic Alterations ◽  
Lineage Tracing ◽  
Cellular Origin ◽  
Regenerative Response ◽  
Peribiliary Glands ◽  
E Cadherin

The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras- and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell–specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-KrasG12D, Tgfbr2flox/flox, and K19CreERT mice (KT-K19CreERT). However, KT-K19CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreERT mice were crossed with CDH1flox/flox mice (KTC-K19CreERT). Surprisingly, KTC-K19CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti–IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.

scholarly journals Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bettina Kunze ◽  
Moritz Middelhoff ◽  
H. Carlo Maurer ◽  
Tatiana Agibalova ◽  
Akanksha Anand ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Secretory Cell ◽  
Notch Receptor ◽  
Neoplastic Progression ◽  
Epithelial Tumor ◽  
Genetic Ablation ◽  
Stem Cell Maintenance ◽  
Cellular Origin ◽  
Tuft Cells ◽  
Notch Activation

AbstractBarrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.

scholarly journals Repopulating Kupffer Cells Originate Directly from Hematopoietic Stem Cells

2020 ◽  
Author(s):  
Xu Fan ◽  
Pei Lu ◽  
Xianghua Cui ◽  
Peng Wu ◽  
Weiran Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Kupffer Cells ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Fate Mapping ◽  
Monocytic Cell ◽  
Hematopoietic Stem ◽  
Cellular Origin

AbstractKupffer cells (KCs) originate from yolk sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at stead state, and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adult remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. In current study, we firstly traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate mapping mouse models, respectively, and found no evidences that repopulating KCs originate from preexisting KCs or MOs. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC depletion in mice, and found that in response to KC depletion, hematopoietic stem cells (HSCs) proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Finally, we traced the fate of HSCs in a HSC-specific fate-mapping mouse model, in context of chronic liver inflammation induced by repeated carbon tetrachloride treatment, and confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided strong in vivo fate-mapping evidences that repopulating KCs originate directly from Hematopoietic stem cells not from preexisting KCs or from MOs.SignificanceThere is a standing controversy in the field regarding the cellular origin of repopulating macrophages. This paper provides strong in vivo fate-mapping evidences that repopulating KCs originate directly from hematopoietic stem cells not from preexisting KCs or from MOs, which presenting a completely novel understanding of the cellular origin of repopulating Kupffer Cells and shedding light on the divergent roles of KCs in liver homeostasis and diseases.

scholarly journals SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27-null mice

2021 ◽  
Vol 118 (7) ◽  
pp. e2017115118
Author(s):  
Veronica Moncho-Amor ◽  
Probir Chakravarty ◽  
Christophe Galichet ◽  
Ander Matheu ◽  
Robin Lovell-Badge ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Mapk Pathway ◽  
Regulatory Region ◽  
Pituitary Tumors ◽  
Lineage Tracing ◽  
Loss Of Function ◽  
Cellular Origin ◽  
Differentiated Cells ◽  
Pituitary Hyperplasia ◽  
Cellular Context

P27, a cell cycle inhibitor, is also able to drive repression of Sox2. This interaction plays a crucial role during development of p27−/− pituitary tumors because loss of one copy of Sox2 impairs tumorigenesis [H. Li et al., Cell Stem Cell 11, 845–852 (2012)]. However, SOX2 is expressed in both endocrine and stem cells (SCs), and its contribution to tumorigenesis in either cell type is unknown. We have thus explored the cellular origin and mechanisms underlying endocrine tumorigenesis in p27−/− pituitaries. We found that pituitary hyperplasia is associated with reduced cellular differentiation, in parallel with increased levels of SOX2 in stem and endocrine cells. Using conditional loss-of-function and lineage tracing approaches, we show that SOX2 is required cell autonomously in p27−/− endocrine cells for these to give rise to tumors, and in SCs for promotion of tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), the target of P27 repressive action. Single cell transcriptomic analysis further reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for tumorigenesis. Altogether, our data highlight different aspects of the role of SOX2 following loss of p27, according to cellular context, and uncover an unexpected SOX2-dependent tumor-promoting role for SCs. Our results imply that targeting SCs, in addition to tumor cells, may represent an efficient antitumoral strategy in certain contexts.

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