scholarly journals Diverse routes of Club cell evolution in lung adenocarcinoma

2021 ◽  
Author(s):  
Yuanyuan Chen ◽  
Reka Toth ◽  
Sara Chocarro ◽  
Dieter Weichenhan ◽  
Joschka Hey ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Lineage Tracing ◽  
Lung Epithelial Cells ◽  
Correct Identification ◽  
High Plasticity ◽  
Cell Of Origin ◽  
Club Cell ◽  
Cell Evolution ◽  
Club Cells ◽  
Lung Regeneration

The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we address the cell-of-origin of LUAD, by employing lineage-tracing mouse models combined with a CRISPR/Cas9 system to induce an oncogenic Eml4-Alk rearrangement in virtually all epithelial cell types of the lung. We find that Club cells give rise to lung tumours with a higher frequency than AT2 cells. Based on whole genome methylome, we identified that tumours retain an epigenetic memory derived from their originating cell type but also develop a tumour-specific pattern regardless of their origin. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, providing a link between lung regeneration and cancer initiation. On both routes, tumours lose their Club cell identity and gain an AT2-like phenotype. Together, this study highlights the role of Club cells in LUAD initiation and unveils key mechanisms conferring LUAD heterogeneity.

scholarly journals Decreased expression of Met during differentiation in rat lung

2016 ◽  
Vol 60 (1) ◽  
Author(s):  
T. Kato ◽  
K. Oka ◽  
T. Nakamura ◽  
A. Ito
Keyword(s):  
Stem Cells ◽  
3D Culture ◽  
Immunofluorescence Assay ◽  
Lung Epithelial Cells ◽  
Alveolar Type ◽  
Cell Marker ◽  
Epithelial Stem Cells ◽  
Club Cell ◽  
Adult Mice ◽  
Lung Epithelial

<p>Organ-specific stem cells play key roles in maintaining the epithelial cell layers of lung. Bronchioalveolar stem cells (BASCs) are distal lung epithelial stem cells of adult mice. Alveolar type 2 (AT2) cells have important functions and serve as progenitor cells of alveolar type 1 (AT1) cells to repair the epithelium when they are injured. Hepatocyte growth factor (HGF) elicits mitogenic, morphogenic, and anti-apoptotic effects on lung epithelial cells through tyrosine phosphorylation of Met receptor, and thus is recognized as a pulmotrophic factor. To understand which cells HGF targets in lung, we identified the cells expressing Met by immunofluorescence assay. Met was strongly expressed in BASCs, which expressed an AT2 cell marker, pro-SP-C, and a club cell marker, CCSP. In alveoli, we found higher expression of Met in primary AT2 than in AT1 cells, which was confirmed using primary AT2 cells. We further examined the mitogenic activity of HGF in AT2-cell-derived alveolar-like cysts (ALCs) in 3D culture. Multicellular ALCs expressed Met, and HGF enhanced the ALC production. Taking these findings together, BASCs could also be an important target for HGF, and HGF-Met signaling could function more potent on cells that have greater multipotency in adult lung.</p>

scholarly journals Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma

2020 ◽  
Vol 13 (10) ◽  
pp. dmm047035
Author(s):  
Dah-Jiun Fu ◽  
Andrea J. De Micheli ◽  
Mallikarjun Bidarimath ◽  
Lora H. Ellenson ◽  
Benjamin D. Cosgrove ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Endometrial Carcinoma ◽  
Marrow Cell ◽  
Cell Types ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Mouse Uterus ◽  
Endometrial Epithelium

ABSTRACTHumans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported that this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here, we describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome and evaluate the contribution of epithelial cells expressing the transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, PAX8+ epithelial cells are responsible for long-term maintenance of both luminal and glandular epithelium. Furthermore, multicolor tracing shows that individual glands and contiguous areas of luminal epithelium are formed by clonal cell expansion. Inactivation of the tumor suppressor genes Trp53 and Rb1 in PAX8+ cells, but not in FOXJ1+ cells, leads to the formation of neoplasms with features of serous endometrial carcinoma, one of the most aggressive types of human endometrial malignancies. Taken together, our results show that the progeny of single PAX8+ cells represents the main source of regeneration of the adult endometrial epithelium. They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma and suggest that PAX8+ cells represent the cell of origin of this neoplasm.

scholarly journals Genetic lineage tracing analysis of the cell of origin of hepatotoxin-induced liver tumors in mice

Hepatology ◽  
2016 ◽  
Vol 64 (4) ◽  
pp. 1163-1177 ◽  
Author(s):  
Soona Shin ◽  
Kirk J. Wangensteen ◽  
Monica Teta-Bissett ◽  
Yue J. Wang ◽  
Elham Mosleh-Shirazi ◽  
...  
Keyword(s):  
Liver Tumors ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Cell Of Origin ◽  
Genetic Lineage Tracing

scholarly journals Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

2019 ◽  
Vol 116 (51) ◽  
pp. 25880-25890 ◽  
Author(s):  
Ileana C. Cuevas ◽  
Subhransu S. Sahoo ◽  
Ashwani Kumar ◽  
He Zhang ◽  
Jill Westcott ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Genetic Model ◽  
Precancerous Lesions ◽  
Lineage Tracing ◽  
Model Systems ◽  
Cancer Type ◽  
Cell Of Origin ◽  
Uterine Carcinosarcoma ◽  
Mesenchymal Transition

Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such asTp53andPten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressorFbxw7in endometrial cancer through defined genetic model systems. Inactivation ofFbxw7andPtenresulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquiredTrp53mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells

2020 ◽  
Vol 12 (536) ◽  
pp. eaaw6003 ◽  
Author(s):  
Anna Julie Peired ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Marco Allinovi ◽  
Francesco Guzzi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Progenitor Cells ◽  
Renal Cell ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Renal Progenitor Cells ◽  
Renal Progenitor

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.

scholarly journals Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

2021 ◽  
Vol 7 (23) ◽  
pp. eabf9141
Author(s):  
Valentin J. A. Barthet ◽  
Martina Brucoli ◽  
Marcus J. G. W. Ladds ◽  
Christoph Nössing ◽  
Christos Kiourtis ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Liver Parenchyma ◽  
Genetically Engineered ◽  
Lineage Tracing ◽  
Binding Motif ◽  
Cell Of Origin ◽  
Ductular Reaction ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Genetically Engineered Mouse Model

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention.

scholarly journals Retrospective cell lineage reconstruction in Humans using short tandem repeats

2017 ◽  
Author(s):  
Liming Tao ◽  
Ofir Raz ◽  
Zipora Marx ◽  
Manjusha Gosh ◽  
Sandra Huber ◽  
...  
Keyword(s):  
Human Cell ◽  
Short Tandem Repeats ◽  
Tandem Repeats ◽  
Single Cells ◽  
Cell Lineage ◽  
Efficient Solutions ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Short Tandem

Cell lineage analysis aims to uncover the developmental history of an organism back to its cell of origin1. Recently, novel in vivo methods and technologies utilizing genome editing enabled important insights into the cell lineages of animals2–8. In contrast, human cell lineage remains restricted to retrospective approaches, which still lack in resolution and cost-efficient solutions. Here we demonstrate a scalable platform for human cell lineage tracing based on Short Tandem Repeats (STRs) targeted by duplex Molecular Inversion Probes (MIPs). With this platform we accurately reproduced a known lineage of DU145 cell lines cells9 and reconstructed lineages of healthy and metastatic single cells from a melanoma patient. The reconstructed trees matched the anatomical and SNV references while adding further refinements. Our platform allowed to faithfully recapitulate lineages of developmental tissue formation in cells from healthy donors. In summary, our lineage discovery platform can profile informative STR somatic mutations efficiently and we provide a solid, high-resolution lineage reconstruction even in challenging low-mutation-rate healthy single cells.

scholarly journals Tfap2b specifies an embryonic melanocyte stem cell population that retains adult multi-fate potential

2021 ◽  
Author(s):  
Alessandro Brombin ◽  
Daniel J. Simpson ◽  
Jana Travnickova ◽  
Hannah R. Brunsdon ◽  
Zhiqiang Zeng ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neural Crest ◽  
Pigment Cell ◽  
Cell Types ◽  
Lineage Tracing ◽  
Stem Cell Population ◽  
Cell Of Origin ◽  
Lineage Markers ◽  
Melanocyte Stem Cell ◽  
Stem Cell Populations

Melanocytes, our pigment producing cells, originate from neural crest-derived progenitors during embryogenesis and from multiple stem cell niches in adult tissues. Although pigmentation traits are known risk-factors for melanoma, we lack lineage markers with which to identify melanocyte stem cell populations and study their function. Here, by combining live-imaging, scRNA-seq and chemical-genetics in zebrafish, we identify the transcription factor Tfap2b as a functional marker for the melanocyte stem cell (MSC) population that resides at the dorsal root ganglia site. Tfap2b is required for only a few late-stage embryonic melanocytes, and instead is essential for MSC-dependent melanocyte regeneration. Our lineage-tracing data reveal that tfap2b-expressing MSCs have multi-fate potential, and are the cell-of-origin for a discrete number of embryonic melanocytes, large patches of adult melanocytes, and two other pigment cell types; iridophores and xanthophores. Hence, Tfap2b confers MSC identity, and thereby distinguishes MSCs from other neural crest and pigment cell lineages.

scholarly journals A role for club cells in smoking-associated lung adenocarcinoma

2021 ◽  
Vol 30 (162) ◽  
pp. 210122
Author(s):  
Sabine J. Behrend ◽  
Georgia A. Giotopoulou ◽  
Magda Spella ◽  
Georgios T. Stathopoulos
Keyword(s):  
Lung Adenocarcinoma ◽  
Relevant Literature ◽  
Cellular Heterogeneity ◽  
Alveolar Type ◽  
Histologic Subtype ◽  
Cellular Origin ◽  
Cells Of Origin ◽  
Club Cells ◽  
Environmental Agents ◽  
Lung Adenocarcinomas

The cellular origin of lung adenocarcinoma remains a focus of intense research efforts. The marked cellular heterogeneity and plasticity of the lungs, as well as the vast variety of molecular subtypes of lung adenocarcinomas perplex the field and account for the extensive variability of experimental results. While most experts would agree on the cellular origins of other types of thoracic tumours, great controversy exists on the tumour-initiating cells of lung adenocarcinoma, since this histologic subtype of lung cancer arises in the distal pulmonary regions where airways and alveoli converge, occurs in smokers as well as nonsmokers, is likely caused by various environmental agents, and is marked by vast molecular and pathologic heterogeneity. Alveolar type II, club, and their variant cells have all been implicated in lung adenocarcinoma progeny and the lineage hierarchies in the distal lung remain disputed. Here we review the relevant literature in this rapidly expanding field, including results from mouse models and human studies. In addition, we present a case for club cells as cells of origin of lung adenocarcinomas that arise in smokers.

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