Novel Strategy for Lineage Tracing of Cancer Stem Cells by Lentiviral Barcoding

AbstractCancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.

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Heritable tumor cell division rate heterogeneity induces clonal dominance

10.1101/097683 ◽

2017 ◽

Author(s):

Margriet M. Palm ◽

Marjet Elemans ◽

Joost B. Beltman

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Lineage Tracing ◽

Hierarchical Organization ◽

Rate Heterogeneity ◽

Division Rate ◽

Cell Division Rate ◽

Mutational Processes ◽

Selection Of

AbstractTumors consist of a hierarchical population of cells that differ in their phenotype and genotype. This hierarchical organization of cells means that a few clones (i.e., cells and several generations of offspring) are abundant while most are rare, which is called clonal dominance. Such dominance also occurred in published in vitro iterated growth and passage experiments with tumor cells in which genetic barcodes were used for lineage tracing. A potential source for such heterogeneity is that dominant clones derive from cancer stem cells with an unlimited self-renewal capacity. Furthermore, ongoing evolution within the growing population may also induce clonal dominance. To understand how clonal dominance developed in the iterated growth and passage experiments, we built a computational model that accurately simulates these experiments. The model simulations reproduced the clonal dominance that developed in in vitro iterated growth and passage experiments when the division rates vary between cells, due to a combination of initial variation and of ongoing mutational processes. In contrast, the experimental results can neither be reproduced with a model that considers random growth and passage, nor with a model based on cancer stem cells. Altogether, our model suggests that in vitro clonal dominance develops due to selection of fast-dividing clones.

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Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a distinct population of cancer stem cells

Scientific Reports ◽

10.1038/s41598-018-37301-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Larissa Mourao ◽

Guillaume Jacquemin ◽

Mathilde Huyghe ◽

Wojciech J. Nawrocki ◽

Naoual Menssouri ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Lineage Tracing ◽

Distinct Population

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

Cancers ◽

10.3390/cancers12123765 ◽

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.

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Novel Strategy to Expand Super-Charged NK Cells with Significant Potential to Lyse and Differentiate Cancer Stem Cells: Differences in NK Expansion and Function between Healthy and Cancer Patients

Frontiers in Immunology ◽

10.3389/fimmu.2017.00297 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 17

Author(s):

Kawaljit Kaur ◽

Jessica Cook ◽

So-Hyun Park ◽

Paytsar Topchyan ◽

Anna Kozlowska ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Nk Cells ◽

Cancer Patients ◽

Significant Potential ◽

Novel Strategy ◽

And Function

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Autophagy in Osteosarcoma Cancer Stem Cells Is Critical Process which Can Be Targeted by the Antipsychotic Drug Thioridazine

Cancers ◽

10.3390/cancers12123675 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3675

Author(s):

Olivier Camuzard ◽

Marie-Charlotte Trojani ◽

Sabine Santucci-Darmanin ◽

Sophie Pagnotta ◽

Véronique Breuil ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cell Lines ◽

Antipsychotic Drug ◽

Bone Cancer ◽

Parental Cell ◽

Interesting Case ◽

Novel Strategy ◽

A Minor ◽

Critical Process

Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties which are able to fuel tumor growth and resist conventional treatments. Autophagy has been described to be upregulated in some CSCs and to play a crucial role by maintaining stem features and promoting resistance to both hostile microenvironments and treatments. Osteosarcoma (OS) is an aggressive bone cancer which mainly affects children and adolescents and autophagy in OS CSCs has been poorly studied. However, this is a very interesting case because autophagy is often deregulated in this cancer. In the present work, we used two OS cell lines showing different autophagy capacities to isolate CSC-enriched populations and to analyze the autophagy in basal and nutrient-deprived conditions. Our results indicate that autophagy is more efficient in CSCs populations compared to the parental cell lines, suggesting that autophagy is a critical process in OS CSCs. We also showed that the antipsychotic drug thioridazine is able to stimulate, and then impair autophagy in both CSC-enriched populations, leading to autosis, a cell death mediated by the Na+/K+ ATPase pump and triggered by dysregulated accumulation of autophagosomes. Taken together, our results indicate that autophagy is very active in OS CSCs and that targeting this pathway to switch their fate from survival to death could provide a novel strategy to eradicate these cells in osteosarcoma.

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Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

Pharmaceutics ◽

10.3390/pharmaceutics13071062 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1062

Author(s):

Adriana G. Quiroz-Reyes ◽

Paulina Delgado-Gonzalez ◽

Jose Francisco Islas ◽

Juan Luis Delgado Gallegos ◽

Javier Humberto Martínez Martínez Garza ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Invasion Pathways ◽

Trail Resistance ◽

Novel Strategy ◽

Cancer Remission

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

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Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.656981 ◽

2021 ◽

Vol 9 ◽

Author(s):

Qilin Li ◽

Ding Xia ◽

Zhihua Wang ◽

Bo Liu ◽

Jing Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Circadian Rhythm ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Bioinformatic Analysis ◽

Vital Role ◽

Prostate Cancer Stem Cells ◽

Novel Strategy ◽

Underlying Mechanisms

Prostate cancer (PCa) cells are heterogeneous, containing a variety of cancer cells with phenotypical and functional discrepancies in the tumor microenvironment, where prostate cancer stem cells (PCSCs) play a vital role in PCa development. Our earlier studies have shown that ALDHhiCD44+ (DP) PCa cells and the corresponding ALDHloCD44– (DN) PCa cells manifest as PCSCs and non-PCSCs, respectively, but the underlying mechanisms regulating stemness of the PCSCs are not completely understood. To tackle this issue, we have performed RNA-Sequencing and bioinformatic analysis in DP (versus DN) cells in this study. We discovered that, PER3 (period circadian regulator 3), a circadian rhythm gene, is significantly downregulated in DP cells. Overexpression of PER3 in DP cells significantly suppressed their sphere- and colony-forming abilities as well as tumorigenicity in immunodeficient hosts. In contrast, knockdown of PER3 in DN cells dramatically promoted their colony-forming and tumor-initiating capacities. Clinically, PER3 is downregulated in human prostate cancer specimens and PER3 expression levels are highly correlated with the prognosis of the PCa patient. Mechanistically, we observed that low levels of PER3 stimulates the expression of BMAL1, leading to the phosphorylation of β-catenin and the activation of the WNT/β-catenin pathway. Together, our results indicate that PER3 negatively regulates stemness of PCSCs via WNT/β-catenin signaling in the tumor microenvironment, providing a novel strategy to treat PCa patients.

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