scholarly journals Lineage Recording Reveals the Phylodynamics, Plasticity and Paths of Tumor Evolution

2021 ◽  
Author(s):  
Dian Yang ◽  
Matthew G Jones ◽  
Santiago Naranjo ◽  
William M Rideout ◽  
Kyung Hoi Joseph Min ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Lineage Tracing ◽  
Rapid Expansion ◽  
Tumor Evolution ◽  
Epigenetic Alterations ◽  
Rna Seq ◽  
Depth Study ◽  
Evolutionary Trajectories ◽  
Hierarchical Nature ◽  
Evolutionary Paths

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth, expansion to neighboring and distal tissues, and therapeutic resistance. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma which enabled us to track tumor evolution from single transformed cells to metastatic tumors at unprecedented resolution. We found that loss of the initial, stable alveolar-type2-like state was accompanied by transient increase in plasticity. This was followed by adoption of distinct fitness associated transcriptional programs which enable rapid expansion and ultimately clonal sweep of rare, stable subclones capable of metastasizing to distant sites. Finally, we showed that tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates tumor progression by creating novel evolutionary paths. Overall, our study elucidates the hierarchical nature of tumor evolution, and more broadly enables the in-depth study of tumor progression.

scholarly journals LOX-1 and cancer: an indissoluble liaison

2021 ◽  
Author(s):  
M. Murdocca ◽  
C. De Masi ◽  
S. Pucci ◽  
R. Mango ◽  
G. Novelli ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Vascular Endothelial Cells ◽  
Transition Process ◽  
Receptor Protein ◽  
Pancreatic Tumors ◽  
Tumor Evolution ◽  
Mesenchymal Transition ◽  
Angiogenic Proteins

AbstractRecently, a strong correlation between metabolic disorders, tumor onset, and progression has been demonstrated, directing new therapeutic strategies on metabolic targets. OLR1 gene encodes the LOX-1 receptor protein, responsible for the recognition, binding, and internalization of ox-LDL. In the past, several studied, aimed to clarify the role of LOX-1 receptor in atherosclerosis, shed light on its role in the stimulation of the expression of adhesion molecules, pro-inflammatory signaling pathways, and pro-angiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. In recent years, LOX-1 upregulation in different tumors evidenced its involvement in cancer onset, progression and metastasis. In this review, we outline the role of LOX-1 in tumor spreading and metastasis, evidencing its function in VEGF induction, HIF-1alpha activation, and MMP-9/MMP-2 expression, pushing up the neoangiogenic and the epithelial–mesenchymal transition process in glioblastoma, osteosarcoma prostate, colon, breast, lung, and pancreatic tumors. Moreover, our studies contributed to evidence its role in interacting with WNT/APC/β-catenin axis, highlighting new pathways in sporadic colon cancer onset. The application of volatilome analysis in high expressing LOX-1 tumor-bearing mice correlates with the tumor evolution, suggesting a closed link between LOX-1 upregulation and metabolic changes in individual volatile compounds and thus providing a viable method for a simple, non-invasive alternative monitoring of tumor progression. These findings underline the role of LOX-1 as regulator of tumor progression, migration, invasion, metastasis formation, and tumor-related neo-angiogenesis, proposing this receptor as a promising therapeutic target and thus enhancing current antineoplastic strategies.

scholarly journals Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

2021 ◽  
Author(s):  
Yannik Bollen ◽  
Ellen Stelloo ◽  
Petra van Leenen ◽  
Myrna van den Bos ◽  
Bas Ponsioen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Cell ◽  
Temporal Dynamics ◽  
De Novo ◽  
Tumor Evolution ◽  
Genome Wide ◽  
Aneuploid Tumor ◽  
Evolutionary Paths ◽  
Tumor Biopsies ◽  
Punctuated Evolution

AbstractCentral to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq—a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.

scholarly journals Criticality in tumor evolution and clinical outcome

2018 ◽  
Vol 115 (47) ◽  
pp. E11101-E11110 ◽  
Author(s):  
Erez Persi ◽  
Yuri I. Wolf ◽  
Mark D. M. Leiserson ◽  
Eugene V. Koonin ◽  
Eytan Ruppin
Keyword(s):  
Clinical Outcome ◽  
Cancer Biology ◽  
Patient Survival ◽  
Fitness Landscape ◽  
Purifying Selection ◽  
Nonlinear Effects ◽  
Tumor Evolution ◽  
Evolutionary Trajectories ◽  
Cancer Types ◽  
Selection Phase

How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML–dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival.

scholarly journals Underwater CAM photosynthesis elucidated by Isoetes genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David Wickell ◽  
Li-Yaung Kuo ◽  
Hsiao-Pei Yang ◽  
Amra Dhabalia Ashok ◽  
Iker Irisarri ◽  
...  
Keyword(s):  
Time Course ◽  
Acid Metabolism ◽  
Arid Environments ◽  
Rna Seq ◽  
Plant Type ◽  
Circadian Control ◽  
Evolutionary Paths ◽  
Cam Photosynthesis ◽  
High Quality Genome ◽  
Bacterial Type

AbstractTo conserve water in arid environments, numerous plant lineages have independently evolved Crassulacean Acid Metabolism (CAM). Interestingly, Isoetes, an aquatic lycophyte, can also perform CAM as an adaptation to low CO2 availability underwater. However, little is known about the evolution of CAM in aquatic plants and the lack of genomic data has hindered comparison between aquatic and terrestrial CAM. Here, we investigate underwater CAM in Isoetes taiwanensis by generating a high-quality genome assembly and RNA-seq time course. Despite broad similarities between CAM in Isoetes and terrestrial angiosperms, we identify several key differences. Notably, Isoetes may have recruited the lesser-known ‘bacterial-type’ PEPC, along with the ‘plant-type’ exclusively used in other CAM and C4 plants for carboxylation of PEP. Furthermore, we find that circadian control of key CAM pathway genes has diverged considerably in Isoetes relative to flowering plants. This suggests the existence of more evolutionary paths to CAM than previously recognized.

scholarly journals The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability

2020 ◽  
Author(s):  
Jennifer Derrien ◽  
Catherine Guérin-Charbonnel ◽  
Victor Gaborit ◽  
Loïc Campion ◽  
Magali Devic ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Environmental Changes ◽  
Cpg Island ◽  
Entropy Change ◽  
Tumor Evolution ◽  
Cancer Evolution ◽  
High Entropy ◽  
Evolutionary Trajectories ◽  
Poor Outcomes

AbstractBackgroundCancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective.ResultsHere, we combined the notions of epipolymorphism and epiallele switching to analyze DNA methylation heterogeneity in MM patients. We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High entropy change is associated with poor outcomes and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability.ConclusionWe propose that disordered methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories.

scholarly journals Characterization of Poldip2 knockout mice: avoiding incorrect gene targeting

2021 ◽  
Author(s):  
Bernard Lassègue ◽  
Sandeep Kumar ◽  
Rohan Mandavilli ◽  
Keke Wang ◽  
Michelle Tsai ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Cell Clone ◽  
Gene Trap ◽  
Rna Seq ◽  
Multifunctional Protein ◽  
Cellular Processes ◽  
Depth Study ◽  
Perinatal Lethality ◽  
Knockout Line

AbstractPOLDIP2 is a multifunctional protein whose roles are only partially understood. Our laboratory previously reported physiological studies performed using a mouse gene trap model, which suffered from two limitations: perinatal lethality in homozygotes and constitutive Poldip2 inactivation. To overcome these limitations, we developed a new conditional floxed Poldip2 model. The first part of the present study shows that our initial floxed mice were affected by an unexpected mutation, which was not readily detected by Southern blotting and traditional PCR. It consisted of a 305 kb duplication around Poldip2 with retention of the wild type allele and could be traced back to the original targeted ES cell clone. We offer simple suggestions to rapidly detect similar accidents, which may affect genome editing using both traditional and CRISPR-based methods. In the second part of the present study, correctly targeted floxed Poldip2 mice were generated and used to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no POLDIP2 expression. To further characterize the effects of Poldip2 ablation in the vasculature, an RNA-seq experiment was performed in constitutive knockout carotid arteries. Results support the involvement of POLDIP2 in multiple cellular processes and provide new opportunities for future in-depth study of its functions.

scholarly journals Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies

2019 ◽  
Vol 116 (7) ◽  
pp. 2662-2671 ◽  
Author(s):  
Chrysovalantis Voutouri ◽  
Nathaniel D. Kirkpatrick ◽  
Euiheon Chung ◽  
Fotios Mpekris ◽  
James W. Baish ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Tumor Evolution ◽  
Combination Therapies ◽  
Tumor Vessel ◽  
Antiangiogenic Treatment ◽  
Antiangiogenic Drugs ◽  
Underlying Mechanisms ◽  
Computational Analyses

Cooption of the host vasculature is a strategy that some cancers use to sustain tumor progression without—or before—angiogenesis or in response to antiangiogenic therapy. Facilitated by certain growth factors, cooption can mediate tumor infiltration and confer resistance to antiangiogenic drugs. Unfortunately, this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood. Here, we analyzed the dynamics of vessel cooption during tumor progression and in response to antiangiogenic treatment in gliomas and brain metastases. We followed tumor evolution during escape from antiangiogenic treatment as cancer cells coopted, and apparently mechanically compressed, host vessels. To gain deeper understanding, we developed a mathematical model, which incorporated compression of coopted vessels, resulting in hypoxia and formation of new vessels by angiogenesis. Even if antiangiogenic therapy can block such secondary angiogenesis, the tumor can sustain itself by coopting existing vessels. Hence, tumor progression can only be stopped by combination therapies that judiciously block both angiogenesis and cooption. Furthermore, the model suggests that sequential blockade is likely to be more beneficial than simultaneous blockade.

scholarly journals Biological Significance of Tumor Heterogeneity in Esophageal Squamous Cell Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1156 ◽  
Author(s):  
Lehang Lin ◽  
De-Chen Lin
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Tumor Heterogeneity ◽  
Three Dimensional ◽  
Biological Significance ◽  
Molecular Characteristics ◽  
Tumor Evolution ◽  
Evolutionary Trajectories

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy, with hitherto dismal clinical outcome. Genomic analyses of patient samples reveal a complex heterogeneous landscape for ESCC, which presents in both intertumor and intratumor forms, manifests at both genomic and epigenomic levels, and contributes significantly to tumor evolution, drug resistance, and metastasis. Here, we review the important molecular characteristics underlying ESCC heterogeneity, with an emphasis on genomic aberrations and their functional contribution to cancer evolutionary trajectories. We further discuss how novel experimental tools, including single-cell sequencing and three-dimensional organoids, may advance our understanding of tumor heterogeneity. Lastly, we suggest that deciphering the mechanisms governing tumor heterogeneity holds the potential to developing precision therapeutics for ESCC patients.

scholarly journals Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

2018 ◽  
Vol 115 (4) ◽  
pp. E610-E619 ◽  
Author(s):  
Onur Basak ◽  
Teresa G. Krieger ◽  
Mauro J. Muraro ◽  
Kay Wiebrands ◽  
Daniel E. Stange ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Number ◽  
Lineage Tracing ◽  
Rapid Expansion ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Proliferating Cells ◽  
Self Renewal ◽  
Genetic Lineage Tracing

The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

scholarly journals TMIC-15. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DIFFERENTIALLY DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ASSOCIATED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi250-vi250
Author(s):  
Patricia Yee ◽  
Yiju Wei ◽  
Zhijun Liu ◽  
Hui Guo ◽  
Umeshkumar Manjibhai Vekariya ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Myeloid Cells ◽  
Treatment Resistance ◽  
Neutrophil Infiltration ◽  
Adult Brain ◽  
Tumor Evolution ◽  
Binding Motif ◽  
Mesenchymal Transition ◽  
The Impact

Abstract Glioblastoma (GBM), the deadliest and most common adult brain malignancy, is molecularly and clinically heterogeneous. The most common subtype (both primary and recurrent), mesenchymal (MES)-GBM, has the worst prognosis and highest treatment resistance. MES-GBM exhibits hyperactive transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in GBMs predicts short survival. Yet, how Hippo-TAZ dysregulation might drive GBM MES transition remains elusive, precluding subtype-specific treatments. Tumor evolution requires signaling dysregulation and co-opting the tumor microenvironment (TME). Understanding GBM heterogeneity was recently complicated by the notion that subtypes vary in TME immune composition. The MES-GBM TME is differentially-distorted in silico, with more tumor-associated macrophages/microglia (TAMs) and neutrophils (TANs). Yet, how TAZ hyperactivity, MES transition, and GBM TME distortion interrelate and impact tumor progression remains unknown. We suspected that TME distortion facilitates immune evasion, MES transition, and tumor progression, worsening treatment responses. To test this, we devised an orthotopic xenograft mouse model phenotypically and histopathologically recapitulating human MES-GBM by expressing constitutively-active TAZ (TAZ4SA) in human GBM cells lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter compared to mice with GBM expressing vector (GBMvector) or mutant TAZ unable to bind its effector, TEAD (GBM4SA-S51A). Moreover, more myeloid cells infiltrate the GBM4SA TME than the GBMvector or GBM4SA-S51A TMEs. While most myeloid cells infiltrating the GBMvector and GBM4SA-S51A TMEs were TAMs, most infiltrating the GBM4SA TME were TANs, suggesting TAZ hyperactivation differentially distorts the TME. Next, to delineate the roles of TANs in GBM4SA tumor progression, mice were depleted of neutrophils by administering Ly6G antibody. Serial blood smears and flow cytometry revealed effective depletion was achieved. We are currently investigating the impact of systemic neutrophil depletion on GBM mesenchymal transition and tumor progression in hopes of informing future GBM clinical management and novel TME-targeted immunotherapies.

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