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Journal of Translational Medicine Feb 2024The global cellular landscape of the tumor microenvironment (TME) combining primary and metastatic liver tumors has not been comprehensively characterized.
BACKGROUND
The global cellular landscape of the tumor microenvironment (TME) combining primary and metastatic liver tumors has not been comprehensively characterized.
METHODS
Based on the scRNA-seq and spatial transcriptomic data of non-tumor liver tissues (NTs), primary liver tumors (PTs) and metastatic liver tumors (MTs), we performed the tissue preference, trajectory reconstruction, transcription factor activity inference, cell-cell interaction and cellular deconvolution analyses to construct a comprehensive cellular landscape of liver tumors.
RESULTS
Our analyses depicted the heterogeneous cellular ecosystems in NTs, PTs and MTs. The activated memory B cells and effector T cells were shown to gradually shift to inhibitory B cells, regulatory or exhausted T cells in liver tumors, especially in MTs. Among them, we characterized a unique group of TCF7+ CD8+ memory T cells specifically enriched in MTs that could differentiate into exhausted T cells likely driven by the p38 MAPK signaling. With regard to myeloid cells, the liver-resident macrophages and inflammatory monocyte/macrophages were markedly replaced by tumor-associated macrophages (TAMs), with TREM2+ and UBE2C+ TAMs enriched in PTs, while SPP1+ and WDR45B+ TAMs in MTs. We further showed that the newly identified WDR45B+ TAMs exhibit an M2-like polarization and are associated with adverse prognosis in patients with liver metastases. Additionally, we addressed that endothelial cells display higher immune tolerance and angiogenesis capacity, and provided evidence for the source of the mesenchymal transformation of fibroblasts in tumors. Finally, the malignant hepatocytes and fibroblasts were prioritized as the pivotal cell populations in shaping the microenvironments of PTs and MTs, respectively. Notably, validation analyses by using spatial or bulk transcriptomic data in clinical cohorts concordantly emphasized the clinical significance of these findings.
CONCLUSIONS
This study defines the ontological and functional heterogeneities in cellular ecosystems of primary and metastatic liver tumors, providing a foundation for future investigation of the underlying cellular mechanisms.
Topics: Humans; Endothelial Cells; Ecosystem; Liver Neoplasms; Gene Expression Profiling; Tumor Microenvironment
PubMed: 38414027
DOI: 10.1186/s12967-024-04947-9 -
Frontiers in Neurology 2022Multiple Sclerosis (MS) is a heterogeneous immune mediated disease of the central nervous system (CNS). Fatigue is one of the most common and disabling symptom of MS. It... (Review)
Review
Multiple Sclerosis (MS) is a heterogeneous immune mediated disease of the central nervous system (CNS). Fatigue is one of the most common and disabling symptom of MS. It interferes with daily activities on the level of cognition and motor endurance. Motor fatigue can either result from lesions in cortical networks or motor pathways ("primary fatigue") or it may be a consequence of detraining with subsequent adaptions of muscle and autonomic function. Programmed exercise interventions are used frequently to increase physical fitness in MS-patients. Studies investigating the effects of training on aerobic capacity, objective endurance and perceived fatigability have yielded heterogenous results, most likely due to the heterogeneity of interventions and patients, but probably also due to the non-uniform pathophysiology of fatigability among MS-patients. The aim of this review is to summarize the current knowledge on the pathophysiology of motor fatigability with special reference to the basic exercise physiology that underlies our understanding of both pathogenesis and treatment interventions.
PubMed: 35968278
DOI: 10.3389/fneur.2022.891415 -
Journal of Translational Medicine Dec 2022Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire...
BACKGROUND
Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction.
METHODS
First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results.
RESULTS
AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin-yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness.
CONCLUSIONS
Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy.
Topics: Animals; Carcinoma, Hepatocellular; Mechanotransduction, Cellular; Liver Neoplasms; Phenotype; Hydrogels; Tumor Microenvironment
PubMed: 36463272
DOI: 10.1186/s12967-022-03778-w -
Scandinavian Journal of Immunology Jul 2019As heterogeneous immune cells, macrophages mount effective responses to various internal and external changes during disease progression. Macrophage polarization, rather... (Review)
Review
As heterogeneous immune cells, macrophages mount effective responses to various internal and external changes during disease progression. Macrophage polarization, rather than macrophage heterogenization, is often used to describe the functional differences between macrophages. While macrophage polarization partially contributes to heterogeneity, it does not completely explain the concept of macrophage heterogeneity. At the same time, there are abundant and sophisticated endogenous and exogenous substances that can affect macrophage heterogeneity. While the research on endogenous factors has been systematically reviewed, the findings on exogenous factors have not been well summarized. Hence, we reviewed the characteristics and inducing factors of heterogeneous macrophages to reveal their functional plasticity as well as their targeting manoeuvreability. In the process of constructing and analysing a network organized by disease-related cells and molecules, paying more attention to heterogeneous macrophages as mediators of this network may help to explore a novel entry point for early prevention of and intervention in disease.
Topics: Animals; Cell Communication; Cell Differentiation; Cell Lineage; Cell Plasticity; Cellular Microenvironment; Humans; Immunomodulation; Macrophages; Receptors, Pattern Recognition
PubMed: 31002413
DOI: 10.1111/sji.12768 -
Mathematical Biosciences and... Mar 2019Circadian rhythms have been observed in behavioral and physiological activities of living things exposed to the natural 24 h light-darkness cycle. Interestingly, even... (Review)
Review
Circadian rhythms have been observed in behavioral and physiological activities of living things exposed to the natural 24 h light-darkness cycle. Interestingly, even under constant darkness, living organisms maintain a robust endogenous circadian rhythm suggesting the existence of an endogenous clock. In mammals, the endogenous clock is located in the suprachiasmatic nucleus (SCN) which is composed of about 20,000 neuronal oscillators. These neuronal oscillators are heterogeneous in their properties, including the intrinsic period, intrinsic amplitude, light information sensitivity, cellular coupling strength, intrinsic amplitudes and the topological links. In this review, we introduce the influence of the heterogeneity of these properties on the two main functions of the SCN, i.e. the free running rhythm in constant darkness and entrainment to the external cycle, based on mathematical models where heterogeneous neuronal oscillators are coupled to form a network. Our findings show that the heterogeneities can alter the free running periods under constant darkness and the entrainment ability to the external cycle for the SCN by controlling a fine balance between flexibility and robustness of the clock. These findings can explain experimental observation, e.g., why the free running periods and entrainment abilities are different between species, and shed light on the heterogeneity of the SCN network.
Topics: Algorithms; Animals; Circadian Clocks; Circadian Rhythm; Computer Simulation; Darkness; Hormones; Humans; Models, Neurological; Neurons; Oscillometry; Suprachiasmatic Nucleus
PubMed: 31137191
DOI: 10.3934/mbe.2019092 -
ACS Earth & Space Chemistry Sep 2023Reduction-oxidation (redox) reactions underlie essentially all biogeochemical cycles. Like most soil properties and processes, redox is spatiotemporally heterogeneous.... (Review)
Review
Reduction-oxidation (redox) reactions underlie essentially all biogeochemical cycles. Like most soil properties and processes, redox is spatiotemporally heterogeneous. However, unlike other soil features, redox heterogeneity has yet to be incorporated into mainstream conceptualizations of soil biogeochemistry. Anoxic microsites, the defining feature of redox heterogeneity in bulk oxic soils and sediments, are zones of oxygen depletion in otherwise oxic environments. In this review, we suggest that anoxic microsites represent a critical component of soil function and that appreciating anoxic microsites promises to advance our understanding of soil and sediment biogeochemistry. In sections 1 and 2, we define anoxic microsites and highlight their dynamic properties, specifically anoxic microsite distribution, redox gradient magnitude, and temporality. In section 3, we describe the influence of anoxic microsites on several key elemental cycles, organic carbon, nitrogen, iron, manganese, and sulfur. In section 4, we evaluate methods for identifying and characterizing anoxic microsites, and in section 5, we highlight past and current approaches to modeling anoxic microsites. Finally, in section 6, we suggest steps for incorporating anoxic microsites and redox heterogeneities more broadly into our understanding of soils and sediments.
PubMed: 37753209
DOI: 10.1021/acsearthspacechem.3c00032 -
Pathobiology : Journal of... 2018Cancer is a spatial and temporal dynamic disease where differently evolving genetic clones are responsible for progression. In this landscape, the genomic heterogeneity... (Review)
Review
Cancer is a spatial and temporal dynamic disease where differently evolving genetic clones are responsible for progression. In this landscape, the genomic heterogeneity of the primary tumours can be captured by deep-sequencing representative spatial samples. However, the recognition of genetic alterations responsible for tumour evolution remains a challenging task. Recently, the "liquid biopsy" was recognized as a powerful real-time approach for the molecular monitoring of this dynamic disease. The term "liquid biopsy" generally refers to the use of circulating (cell-free) tumour DNA (ctDNA) and circulating tumour cells (CTCs) as non-invasive biomarkers for the early diagnosis, prognosis, monitoring of clinical progression, and response to treatment in different types of tumours, including the highly genomic heterogeneous breast cancer. The implementation and standardization of both approaches are still needed to achieve the required sensitivity and specificity to successfully analyze heterogenous tumours, but pivotal studies, in particular those concerning colorectal cancer, have shown the feasibility and usefulness of liquid biopsy for monitoring the Darwinian clonal evolution from an early to a metastatic stage.
Topics: Breast Neoplasms; Circulating Tumor DNA; Colonic Neoplasms; DNA, Neoplasm; Female; Genomics; Humans; Liquid Biopsy; Mutation; Neoplastic Cells, Circulating; Prognosis
PubMed: 28614831
DOI: 10.1159/000473882 -
Nanomaterials (Basel, Switzerland) Jul 2022As the demands for improved performance of integrated circuit (IC) chips continue to increase, while technology scaling driven by Moore's law is becoming extremely... (Review)
Review
As the demands for improved performance of integrated circuit (IC) chips continue to increase, while technology scaling driven by Moore's law is becoming extremely challenging, if not impractical or impossible, heterogeneous integration (HI) emerges as an attractive pathway to further enhance performance of Si-based complementary metal-oxide-semiconductor (CMOS) chips. The underlying basis for using HI technologies and structures is that IC performance goes well beyond classic logic functions; rather, functionalities and complexity of smart chips span across the full information chain, including signal sensing, conditioning, processing, storage, computing, communication, control, and actuation, which are required to facilitate comprehensive human-world interactions. Therefore, HI technologies can bring in more function diversifications to make system chips smarter within acceptable design constraints, including costs. Over the past two decades or so, a large number of HI technologies have been explored to increase heterogeneities in materials, technologies, devices, circuits, and system architectures, making it practically impossible to provide one single comprehensive review of everything in the field in one paper. This article chooses to offer a topical overview of selected HI structures that have been validated in CMOS platforms, including a stacked-via vertical magnetic-cored inductor structure in CMOSs, a metal wall structure in the back end of line (BEOL) of CMOSs to suppress global flying noises, an above-IC graphene nano-electromechanical system (NEMS) switch and nano-crossbar array electrostatic discharge (ESD) protection structure, and graphene ESD interconnects.
PubMed: 35889564
DOI: 10.3390/nano12142340 -
Diagnostics (Basel, Switzerland) Aug 2021Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends... (Review)
Review
Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends on the continuity of events resulting in a sequence of well-defined disease stages, from monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma (SMM) to symptomatic multiple myeloma (MM). Evolution of a pre-malignant cell into a malignant cell, as well as further tumor progression, dissemination, and relapse, require development of multiple driver lesions conferring selective advantage of the dominant clone and allowing subsequent evolution under selective pressure of microenvironment and treatment. This process of natural selection facilitates tumor plasticity leading to the formation of genetically complex and heterogenous tumors that are notoriously difficult to treat. Better understanding of the mechanisms underlying tumor evolution in MM and identification of lesions driving the evolution from the premalignant clone is therefore a key to development of effective treatment and long-term disease control. Here, we review recent advances in clonal evolution patterns and genomic landscape dynamics of MM, focusing on their clinical implications.
PubMed: 34573876
DOI: 10.3390/diagnostics11091534 -
Frontiers in Oncology 2021Acute Myeloid Leukaemia (AML) is a phenotypically and genetically heterogenous blood cancer characterised by very poor prognosis, with disease relapse being the primary... (Review)
Review
Acute Myeloid Leukaemia (AML) is a phenotypically and genetically heterogenous blood cancer characterised by very poor prognosis, with disease relapse being the primary cause of treatment failure. AML heterogeneity arise from different genetic and non-genetic sources, including its proposed hierarchical structure, with leukemic stem cells (LSCs) and progenitors giving origin to a variety of more mature leukemic subsets. Recent advances in single-cell molecular and phenotypic profiling have highlighted the intra and inter-patient heterogeneous nature of AML, which has so far limited the success of cell-based immunotherapy approaches against single targets. Machine Learning (ML) can be uniquely used to find non-trivial patterns from high-dimensional datasets and identify rare sub-populations. Here we review some recent ML tools that applied to single-cell data could help disentangle cell heterogeneity in AML by identifying distinct core molecular signatures of leukemic cell subsets. We discuss the advantages and limitations of unsupervised and supervised ML approaches to cluster and classify cell populations in AML, for the identification of biomarkers and the design of personalised therapies.
PubMed: 33996595
DOI: 10.3389/fonc.2021.666829