Abstract Background In Hong Kong, about 30% of non-small cell lung cancer patients have never smoked tobacco. Among women, 83% are never-smokers and their histological type is invariably ...adenocarcinoma with 70% incidence of epidermal growth factor receptor ( EGFR ) mutation. The present study focuses on the microRNA (miRNA) expression profiles of this important subset of lung cancer. Methods Paired samples collected from the lung cancer tissue and adjacent normal lung parenchyma of 10 non-smoking patients with lung adenocarcinoma were profiled by miRNA microarray. Results were validated by quantitative reverse transcription polymerase chain reaction. Transfected cell viability assays were applied to determine the effects of candidate miRNAs on lung cancer cells. Results Comparing paired lung cancer tissue with adjacent normal lung parenchyma, hsa-miR-126∗ , hsa-miR-145 , hsa-miR-21 , hsa-miR-182 , hsa-miR-183 and hsa-miR-210 were found to be the most differentially expressed miRNAs. Most interestingly, an obvious inhibition of cell growth was observed in the EGFR mutant lung adenocarcinoma after transfection of hsa-pre-miR-145. Conclusions Our study is the first report to connect miR-182 to lung cancer. Our results also show that restoration of tumour suppressor hsa-miR-145 inhibits cancer cell growth in EGFR mutant lung adenocarcinoma. Further study on these specific differentially expressed miRNAs may provide important information on peculiar tumourigenetic pathways and may identify useful biomarkers.
MicroRNAs (miRNAs) are emerging as important modulators in cellular pathways and they appear to play a key role in tumorigenesis. MiR-145 is downregulated in several human malignancies, including ...lung cancer, but the responsible molecular mechanisms remain unclear. We previously reported that restoration of hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. This study showed that hsa-miR-145 targets EGFR and nucleoside diphosphate linked moiety X-type motif 1 (NUDT1 or MTH1) in lung adenocarinoma cells. The mRNA expressions of EGFR and NUDT1 were significantly downregulated after miR-145 transfection in human lung adenocarcinoma cells. Our results demonstrated miR-145 in the negative regulation of EGFR and NUDT1 expressions at both mRNA and protein levels. Further analysis showed that miR-145 has the ability to inhibit cell proliferation on transfected lung adenocarcinoma cells over three time points (24, 48 and 72 hours). Upregulation of miR-145 appeared to be an important gene regulation mechanism for the proliferation of lung adenocarcinoma cells and it correlated strongly with the downregulation of EGFR and NUDT1. Interestingly, our study revealed that the altered proliferation in lung cancer cells is not accompanied by changes in apoptosis. Our findings provided new insight into the complex regulating pathway comprising of miR-145, EGFR, NUDT1 and other unknown factors which function in cell proliferation but not in apoptosis. Understanding miR-145's targets and its regulating pathways may lead to new therapeutic strategies for lung adenocarcinoma.
The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells. Tissue phagocytes share several cell surface markers, phagocytic capability and myeloid classification; ...however, the factors that regulate the differentiation, homeostasis and function of macrophages and dendritic cells remain largely unknown. The purpose of this manuscript is to review the tools that are currently available and those that are under development to study the origin and function of mononuclear phagocytes.
The commensal microbiota impacts specific immune cell populations and their functions at peripheral sites, such as gut mucosal tissues. However, it remains unknown whether gut microbiota control ...immunity through regulation of hematopoiesis at primary immune sites. We reveal that germ-free mice display reduced proportions and differentiation potential of specific myeloid cell progenitors of both yolk sac and bone marrow origin. Homeostatic innate immune defects may lead to impaired early responses to pathogens. Indeed, following systemic infection with Listeria monocytogenes, germ-free and oral-antibiotic-treated mice display increased pathogen burden and acute death. Recolonization of germ-free mice with a complex microbiota restores defects in myelopoiesis and resistance to Listeria. These findings reveal that gut bacteria direct innate immune cell development via promoting hematopoiesis, contributing to our appreciation of the deep evolutionary connection between mammals and their microbiota.
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•Germ-free animals display a global defect in peripheral innate immune cells•Gut microbes impact both yolk sac- and stem cell-derived myeloid cell development•The microbiota promotes host resistance to systemic bacterial infection•Oral antibiotics impair myelopoiesis, causing transient immune suppression
Khosravi et al. show that commensal microbiota direct immune development by promoting hematopoiesis within primary and secondary lymphoid organs, which is essential for host resistance to pathogenic microbes. Specifically, gut microbes impact both yolk sac- and stem cell-derived myeloid cell development and promote early resistance to systemic Listeria monocytogenes infection.
Podocytes are highly specialized epithelial cells that surround the capillaries of the glomeruli in the kidney. Together with the glomerular endothelial cells, these postmitotic cells are responsible ...for regulating filtrate from the circulating blood with their organized network of interdigitating foot processes that wrap around the glomerular basement membrane. Although podocyte injury and subsequent loss is the hallmark of many glomerular diseases, recent evidence suggests that the cell-cell communication between podocytes and other glomerular and nonglomerular cells is critical for the development and progression of kidney disease. In this review, we highlight these key cellular pathways of communication and how they might be a potential target for therapy in glomerular disease. We also postulate that podocytes might serve as a central hub for communication in the kidney under basal conditions and in response to cellular stress, which may have implications for the development and progression of glomerular diseases.
Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have ...been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.
Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC ...niche. We defined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin(+) niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the ...heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.
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•Most small cell lung cancer (SCLC) tumors share a small PLCG2-high subpopulation•This PLCG2-high SCLC subpopulation is linked to metastasis and poor prognosis•SCLC is enriched in profibrotic and immunosuppressive monocytes/macrophages•The presence of myeloid cells is associated with the PLCG2-high SCLC subpopulation
Chan et al. use single-cell transcriptome sequencing and imaging techniques to study the heterogeneity and tumor microenvironment of clinical small cell lung cancer specimens. This analysis identifies a PLCG2-high-expressing subpopulation linked to metastasis and poor prognosis, and an enrichment of a monocyte/macrophage population with a profibrotic, immunosuppressive phenotype.
Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in ...neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.
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•Pharmacologic modulation of splicing enhances immune checkpoint blockade efficacy•RBM39 degradation and type I PRMT inhibition are well tolerated by immune cells•Splicing perturbation induces splicing-derived neoepitopes that are immunogenic•Rigorous framework for the identification of splicing-derived antigenic peptides
By provoking production of “neoantigens” that are recognized by immune cells, drugs that modulate RNA splicing can enhance cancer immunotherapy.
Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization ...of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.
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