-
Clinical and Translational Medicine Nov 2022Brain malignancies encompass gliomas and brain metastases originating from extracranial tumours including lung cancer. Approximately 50% of patients with lung...
BACKGROUND
Brain malignancies encompass gliomas and brain metastases originating from extracranial tumours including lung cancer. Approximately 50% of patients with lung adenocarcinoma (LUAD) will eventually develop brain metastases. However, the specific characteristics of gliomas and lung-to-brain metastases (LC) are largely unknown.
METHODS
We applied single-cell RNA sequencing to profile immune and nonimmune cells in 4 glioma and 10 LC samples.
RESULTS
Our analysis revealed that tumour microenvironment (TME) cells are present in heterogeneous subpopulations. LC reprogramed cells into immune suppressed state, including microglia, macrophages, endothelial cells, and CD8 T cells, with unique cell proportions and gene signatures. Particularly, we identified that a subset of macrophages was associated with poor prognosis. ROS (reactive oxygen species)-producing neutrophils was found to participant in angiogenesis. Furthermore, endothelial cells participated in active communication with fibroblasts. Metastatic epithelial cells exhibited high heterogeneity in chromosomal instability (CIN) and cell population.
CONCLUSIONS
Our findings provide a comprehensive understanding of the heterogenicity of the tumor microenvironment and tumour cells and it will be crucial for successful immunotherapy development for brain metastasis of lung cancer.
Topics: Humans; CD8-Positive T-Lymphocytes; Endothelial Cells; Glioma; Brain Neoplasms; Lung Neoplasms; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 36336787
DOI: 10.1002/ctm2.1101 -
International Journal of Cancer Oct 2022Lymph node metastasis is the common metastasis route of gastric cancer. However, until now, heterogeneities of tumor cells and tumor microenvironment in primary tumors...
Lymph node metastasis is the common metastasis route of gastric cancer. However, until now, heterogeneities of tumor cells and tumor microenvironment in primary tumors (PT) and metastatic lymph nodes (MLN) of gastric cancer (GC) remains uncharacterized. In our study, single cell RNA sequencing was performed on tissues from PT and MLN of gastric cancer. Trajectory analysis and function enrichment analyses were conducted to decode the underlying mechanisms contributing to LN metastasis of gastric cancer. Heterogeneous composition of immune cells and distinct intercellular interactions in PT and MLN were analyzed. Based on the generated single cell transcriptome profiles, dynamics of gene expressions in cancer cells between PT and MLN were characterized. Moreover, we reconstructed the developmental trajectory of GC cells' metastasis to LN and identified two subtypes of GC cells with distinct potentials of having malignant biological behaviors. We characterized the repression of neutrophil polarization associated genes, like LCN2, which would contribute to LN metastasis, and histochemistry experiments validated our findings. Additionally, heterogeneity in neutrophils, rather than macrophages, was characterized. Immune checkpoint associated interaction of SPP1 was found active in MLN. In conclusion, we decode the dynamics of tumor cells during LN metastasis in GC and to identify a subtype of GC cells with potentials of LN metastasis. Our data indicated that the disordering the neutrophils polarization and maturation and the activation of immune checkpoint SPP1 might contribute to LN metastasis in GC, providing a novel insight on the mechanism and potential therapeutic targets of LN metastasis in GC.
Topics: Humans; Lymph Nodes; Lymphatic Metastasis; RNA-Seq; Stomach Neoplasms; Tumor Microenvironment
PubMed: 35716132
DOI: 10.1002/ijc.34172 -
International Journal of Molecular... Apr 2023Ribosomes, in general, are viewed as constitutive macromolecular machines where protein synthesis takes place; however, this view has been recently challenged,... (Review)
Review
Ribosomes, in general, are viewed as constitutive macromolecular machines where protein synthesis takes place; however, this view has been recently challenged, supporting the hypothesis of ribosome specialization and opening a completely new field of research. Recent studies have demonstrated that ribosomes are heterogenous in their nature and can provide another layer of gene expression control by regulating translation. Heterogeneities in ribosomal RNA and ribosomal proteins that compose them favor the selective translation of different sub-pools of mRNAs and functional specialization. In recent years, the heterogeneity and specialization of ribosomes have been widely reported in different eukaryotic study models; however, few reports on this topic have been made on protozoa and even less on protozoa parasites of medical importance. This review analyzes heterogeneities of ribosomes in protozoa parasites highlighting the specialization in their functions and their importance in parasitism, in the transition between stages in their life cycle, in the change of host and in response to environmental conditions.
Topics: Animals; Parasites; Protein Biosynthesis; Ribosomes; Ribosomal Proteins; RNA, Ribosomal
PubMed: 37108644
DOI: 10.3390/ijms24087484 -
Clinical Cancer Research : An Official... Apr 2019Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs),...
PURPOSE
Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC.
EXPERIMENTAL DESIGN
Single-cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells from 2 low-grade IPMNs (LGD-IPMNs), 2 high-grade IPMNs (HGD-IPMN), and 2 PDACs (all surgically resected).
RESULTS
Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. Although HGD-IPMNs expressed many core signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a proinflammatory immune component was readily seen in low-grade IPMNs, composed of cytotoxic T cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis.
CONCLUSIONS
This study demonstrates the ability to perform high-resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single-cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneities that accompany early cancer pathogenesis and might be a useful substrate to identify targets for cancer interception..
Topics: Adenocarcinoma, Mucinous; Carcinoma, Pancreatic Ductal; Disease Progression; Humans; Pancreatic Neoplasms; Phenotype; Tumor Microenvironment
PubMed: 30385653
DOI: 10.1158/1078-0432.CCR-18-1955 -
Chronic Stress (Thousand Oaks, Calif.) 2020Genome-wide association studies (GWAS) have been performed for many psychiatric disorders and revealed a complex polygenic architecture linking mental and physical... (Review)
Review
Genome-wide association studies (GWAS) have been performed for many psychiatric disorders and revealed a complex polygenic architecture linking mental and physical health phenotypes. Psychiatric diagnoses are often heterogeneous, and several layers of trait heterogeneity may contribute to detection of genetic risks per disorder or across multiple disorders. In this review, we discuss these heterogeneities and their consequences on the discovery of risk loci using large-scale genetic data. We primarily highlight the ways in which sex and diagnostic complexity contribute to risk locus discovery in schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorder, posttraumatic stress disorder, major depressive disorder, obsessive-compulsive disorder, Tourette's syndrome and chronic tic disorder, anxiety disorders, suicidality, feeding and eating disorders, and substance use disorders. Genetic data also have facilitated discovery of clinically relevant subphenotypes also described here. Collectively, GWAS of psychiatric disorders revealed that the understanding of heterogeneity, polygenicity, and pleiotropy is critical to translate genetic findings into treatment strategies.
PubMed: 32518889
DOI: 10.1177/2470547020924844 -
Frontiers in Immunology 2023Colorectal cancer (CRC) is a highly heterogeneous cancer. The molecular and cellular characteristics differ between the colon and rectal cancer type due to the...
Integration of single-cell RNA sequencing and bulk RNA transcriptome sequencing reveals a heterogeneous immune landscape and pivotal cell subpopulations associated with colorectal cancer prognosis.
INTRODUCTION
Colorectal cancer (CRC) is a highly heterogeneous cancer. The molecular and cellular characteristics differ between the colon and rectal cancer type due to the differences in their anatomical location and pathological properties. With the advent of single-cell sequencing, it has become possible to analyze inter- and intra-tumoral tissue heterogeneities.
METHODS
A comprehensive CRC immune atlas, comprising 62,398 immune cells, was re-structured into 33 immune cell clusters at the single-cell level. Further, the immune cell lineage heterogeneity of colon, rectal, and paracancerous tissues was explored. Simultaneously, we characterized the TAM phenotypes and analyzed the transcriptomic factor regulatory network of each macrophage subset using SCENIC. In addition, monocle2 was used to elucidate the B cell developmental trajectory. The crosstalk between immune cells was explored using CellChat and the patterns of incoming and outgoing signals within the overall immune cell population were identified. Afterwards, the bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) were combined and the relative infiltration abundance of the identified subpopulations was analyzed using CIBERSORT. Moreover, cell composition patterns could be classified into five tumor microenvironment (TME) subtypes by employing a consistent non-negative matrix algorithm. Finally, the co-expression and interaction between SPP1+TAMs and Treg cells in the tumor microenvironment were analyzed by multiplex immunohistochemistry.
RESULTS
In the T cell lineage, we found that CXCL13+T cells were more widely distributed in colorectal cancer tissues, and the proportion of infiltration was increased. In addition, Th17 was found accounted for the highest proportion in CD39+CD101+PD1+T cells. Mover, Ma1-SPP1 showed the characteristics of M2 phenotypes and displayed an increased proportion in tumor tissues, which may promote angiogenesis. Plasma cells (PCs) displayed a significantly heterogeneous distribution in tumor as well as normal tissues. Specifically, the IgA+ PC population could be shown to be decreased in colorectal tumor tissues whereas the IgG+ PC one was enriched. In addition, information flow mediated by SPP1 and CD44, regulate signaling pathways of tumor progression. Among the five TME subtypes, the TME-1 subtype displayed a markedly reduced proportion of T-cell infiltration with the highest proportion of macrophages which was correlated to the worst prognosis. Finally, the co-expression and interaction between SPP1+TAMs and Treg cells were observed in the CD44 enriched region.
DISCUSSION
The heterogeneity distribution and phenotype of immune cells were analyzed in colon cancer and rectal cancer at the single-cell level. Further, the prognostic role of major tumor-infiltrating lymphocytes and TME subtypes in CRC was evaluated by integrating bulk RNA. These findings provide novel insight into the immunotherapy of CRC.
Topics: Transcriptome; Prognosis; Colorectal Neoplasms; Rectal Neoplasms; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 37675100
DOI: 10.3389/fimmu.2023.1184167 -
Cancers Feb 2022(1) Background: Hyperthermia in oncology conventionally seeks the homogeneous heating of the tumor mass. The expected isothermal condition is the basis of the dose... (Review)
Review
(1) Background: Hyperthermia in oncology conventionally seeks the homogeneous heating of the tumor mass. The expected isothermal condition is the basis of the dose calculation in clinical practice. My objective is to study and apply a heterogenic temperature pattern during the heating process and show how it supports radiotherapy. (2) Methods: The targeted tissue's natural electric and thermal heterogeneity is used for the selective heating of the cancer cells. The amplitude-modulated radiofrequency current focuses the energy absorption on the membrane rafts of the malignant cells. The energy partly "nonthermally" excites and partly heats the absorbing protein complexes. (3) Results: The excitation of the transmembrane proteins induces an extrinsic caspase-dependent apoptotic pathway, while the heat stress promotes the intrinsic caspase-dependent and independent apoptotic signals generated by mitochondria. The molecular changes synergize the method with radiotherapy and promote the abscopal effect. The mild average temperature (39-41 °C) intensifies the blood flow for promoting oxygenation in combination with radiotherapy. The preclinical experiences verify, and the clinical studies validate the method. (4) Conclusions: The heterogenic, molecular targeting has similarities with DNA strand-breaking in radiotherapy. The controlled energy absorption allows using a similar energy dose to radiotherapy (J/kg). The two therapies are synergistically combined.
PubMed: 35205649
DOI: 10.3390/cancers14040901 -
Frontiers in Immunology 2022Innate lymphoid cells (ILCs) are a heterogenous population of the innate immune system, enriched at mucosal surfaces and are pivotal regulators of immune homeostasis.... (Review)
Review
Innate lymphoid cells (ILCs) are a heterogenous population of the innate immune system, enriched at mucosal surfaces and are pivotal regulators of immune homeostasis. ILCs are the innate counterpart of T cells. Like T cells, ILC subsets are highly plastic with their composition and function controlled by alterations in their microenvironment. This plasticity allows for the trans-differentiation between the subsets to rapidly respond to their immune environment. The tumor microenvironment (TME) is a heterogeneous milieu characterized by different cytokines and growth factors. Through interaction with the tumor microenvironment, ILCs can transdifferentiate into different subsets resulting in pro or anti-tumor immunity. Thus, studying ILC plasticity might result in new therapeutic approaches for cancer therapy. In this review, we summarize current findings of the functional and plastic heterogeneity of ILCs in homeostasis as well as disease settings with a specific focus on cancer. We specifically highlight tumor-driven plasticity and how ILC-induced inflammation can impact the tumor microenvironment and anti-tumor immunity.
Topics: Humans; Immunity, Innate; Lymphocytes; Neoplasms; Plastics; Tumor Microenvironment
PubMed: 35663967
DOI: 10.3389/fimmu-13-886520 -
Biomedicines Jun 2023The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 () is the largest of the genetically... (Review)
Review
The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 () is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of AML patients.
PubMed: 37509445
DOI: 10.3390/biomedicines11071805 -
Frontiers in Oncology 2020Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options.... (Review)
Review
Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra- and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.
PubMed: 32269966
DOI: 10.3389/fonc.2020.00388