-
Science Advances May 2016Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed... (Review)
Review
Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.
Topics: Animals; Energy Metabolism; Humans; Macromolecular Substances; Metabolic Networks and Pathways; Mitochondria; Molecular Targeted Therapy; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction
PubMed: 27386546
DOI: 10.1126/sciadv.1600200 -
The Journal of Clinical Investigation Feb 2023Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic...
Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic association between genes of innate immunity and AMD, genome-to-phenome relationships are low, suggesting a critical contribution of environmental triggers of disease. Possible insight comes from the observation that a past history of infection with pathogens such as Chlamydia pneumoniae, or other systemic inflammation, can predispose to nvAMD in later life. Using a mouse model of nvAMD with prior C. pneumoniae infection, endotoxin exposure, and genetic ablation of distinct immune cell populations, we demonstrated that peripheral infections elicited epigenetic reprogramming that led to a persistent memory state in retinal CX3CR1+ mononuclear phagocytes (MNPs). The immune imprinting persisted long after the initial inflammation had subsided and ultimately exacerbated choroidal neovascularization in a model of nvAMD. Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identified activating transcription factor 3 (ATF3) as a central mediator of retina-resident MNP reprogramming following peripheral inflammation. ATF3 polarized MNPs toward a reparative phenotype biased toward production of proangiogenic factors in response to subsequent injury. Therefore, a past history of bacterial endotoxin-induced inflammation can lead to immunological reprograming within CNS-resident MNPs and aggravate pathological angiogenesis in the aging retina.
Topics: Humans; Microglia; Retina; Choroidal Neovascularization; Macular Degeneration; Inflammation
PubMed: 36787231
DOI: 10.1172/JCI159757 -
Current Opinion in Genetics &... Oct 2018Genome editing with engineered nucleases (zinc finger, TAL effector, or CRISPR/Cas9-based) enables `write' access to regulatory programs executed by primary human cells.... (Review)
Review
Genome editing with engineered nucleases (zinc finger, TAL effector, or CRISPR/Cas9-based) enables `write' access to regulatory programs executed by primary human cells. A decade of its clinical development, along with a reduction of conventional gene therapy to medical and commercial practice, has made cell reprogramming via editing a viable clinical modality. Reviewed here are the first examples of this to enter the clinic: ex vivo edited T cells for infectious disease and cancer, and hematopoietic stem/progenitor cells for the hemoglobinopathies. Three ongoing developments will ensure that the range of edited and reprogrammed cells to enter the clinic, and the scope of target indications, will grow markedly in the next five years: our ability to identify disease-relevant targets in noncoding regulatory DNA, which is uniquely suited for editing-based cell program control; recent reduction to clinical practice of in vivo editing; and progress in engineering and manufacture of differentiated cells from pluripotent progenitors.
Topics: CRISPR-Cas Systems; Cellular Reprogramming; Gene Editing; Genetic Engineering; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans
PubMed: 29879620
DOI: 10.1016/j.gde.2018.05.005 -
Physiological Reviews Jan 2019The discovery of somatic cell nuclear transfer proved that somatic cells can carry the same genetic code as the zygote, and that activating parts of this code are... (Review)
Review
The discovery of somatic cell nuclear transfer proved that somatic cells can carry the same genetic code as the zygote, and that activating parts of this code are sufficient to reprogram the cell to an early developmental state. The discovery of induced pluripotent stem cells (iPSCs) nearly half a century later provided a molecular mechanism for the reprogramming. The initial creation of iPSCs was accomplished by the ectopic expression of four specific genes (OCT4, KLF4, SOX2, and c-Myc; OSKM). iPSCs have since been acquired from a wide range of cell types and a wide range of species, suggesting a universal molecular mechanism. Furthermore, cells have been reprogrammed to iPSCs using a myriad of methods, although OSKM remains the gold standard. The sources for iPSCs are abundant compared with those for other pluripotent stem cells; thus the use of iPSCs to model the development of tissues, organs, and other systems of the body is increasing. iPSCs also, through the reprogramming of patient samples, are being used to model diseases. Moreover, in the 10 years since the first report, human iPSCs are already the basis for new cell therapies and drug discovery that have reached clinical application. In this review, we examine the generation of iPSCs and their application to disease and development.
Topics: Animals; Cell Differentiation; Cell- and Tissue-Based Therapy; Cells, Cultured; Humans; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4; Models, Biological; Pluripotent Stem Cells
PubMed: 30328784
DOI: 10.1152/physrev.00039.2017 -
Metabolites Jan 2021Cancer cells face various metabolic challenges during tumor progression, including growth in the nutrient-altered and oxygen-deficient microenvironment of the primary... (Review)
Review
Cancer cells face various metabolic challenges during tumor progression, including growth in the nutrient-altered and oxygen-deficient microenvironment of the primary site, intravasation into vessels where anchorage-independent growth is required, and colonization of distant organs where the environment is distinct from that of the primary site. Thus, cancer cells must reprogram their metabolic state in every step of cancer progression. Metabolic reprogramming is now recognized as a hallmark of cancer cells and supports cancer growth. Elucidating the underlying mechanisms of metabolic reprogramming in cancer cells may help identifying cancer targets and treatment strategies. This review summarizes our current understanding of metabolic reprogramming during cancer progression and metastasis, including cancer cell adaptation to the tumor microenvironment, defense against oxidative stress during anchorage-independent growth in vessels, and metabolic reprogramming during metastasis.
PubMed: 33401771
DOI: 10.3390/metabo11010028 -
Biochimica Et Biophysica Acta. Reviews... Aug 2021Recent studies have established that tumors can reprogram the pathways involved in nutrient uptake and metabolism to withstand the altered biosynthetic, bioenergetics... (Review)
Review
Recent studies have established that tumors can reprogram the pathways involved in nutrient uptake and metabolism to withstand the altered biosynthetic, bioenergetics and redox requirements of cancer cells. This phenomenon is called metabolic reprogramming, which is promoted by the loss of tumor suppressor genes and activation of oncogenes. Because of alterations and perturbations in multiple metabolic pathways, renal cell carcinoma (RCC) is sometimes termed as a "metabolic disease". The majority of metabolic reprogramming in renal cancer is caused by the inactivation of von Hippel-Lindau (VHL) gene and activation of the Ras-PI3K-AKT-mTOR pathway. Hypoxia-inducible factor (HIF) and Myc are other important players in the metabolic reprogramming of RCC. All types of RCCs are associated with reprogramming of glucose and fatty acid metabolism and the tricarboxylic acid (TCA) cycle. Metabolism of glutamine, tryptophan and arginine is also reprogrammed in renal cancer to favor tumor growth and oncogenesis. Together, understanding these modifications or reprogramming of the metabolic pathways in detail offer ample opportunities for the development of new therapeutic targets and strategies, discovery of biomarkers and identification of effective tumor detection methods.
Topics: Animals; Carcinoma, Renal Cell; Cellular Reprogramming; Disease Progression; Energy Metabolism; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Signal Transduction
PubMed: 33965513
DOI: 10.1016/j.bbcan.2021.188559 -
Nature Jul 2023Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary...
Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolarĀ epithelial type II (AT2) cells. Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour.
Topics: Humans; Adenocarcinoma of Lung; Cellular Reprogramming; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Stem Cells; Extracellular Signal-Regulated MAP Kinases
PubMed: 37468622
DOI: 10.1038/s41586-023-06324-w -
Nature Communications Nov 2022Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents...
Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
Topics: Animals; Mice; Proteome; Mitochondria; Macrophages; Mitophagy; Peptide Hydrolases; Lysosomes
PubMed: 36443305
DOI: 10.1038/s41467-022-34632-8 -
Journal of Experimental & Clinical... Nov 2023Lines of evidence indicated that, immune checkpoints (ICs) inhibitors enhanced T cell immune response to exert anti-tumor effects. However, T cell exhaustion has been so...
BACKGROUND
Lines of evidence indicated that, immune checkpoints (ICs) inhibitors enhanced T cell immune response to exert anti-tumor effects. However, T cell exhaustion has been so far a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear.
METHODS
The correlation between arginase-1 (ARG1) and T cells was computed based on the colorectal cancer patients in TCGA database. In vitro, we observed that GDNPs reprogrammed TAMs inhibited ARG1 release and ultimately ameliorated T cell exhaustion according to several techniques including WB, PCR, ELISA and flow cytometry. We also used an in vivo MC38 tumor-bearing model and administered GDNPs to assess their anti-tumor effects through multiple indices. The mechanism that GDNPs improved T cell exhaustion was further clarified using the bioinformatics tools and flow cytometry.
RESULTS
GDNPs reprogramed TAMs via reducing ARG1 production. Moreover, normalized arginine metabolism ameliorated T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8 T cells expansion.
CONCLUSIONS
By regulating the mTOR-T-bet axis, GDNPs reprogramed macrophages to regulate ARG1 release, which further ameliorated T cell exhaustion in TME. These findings provided new insights into comprehending the mechanisms underlying the mitigation of T cell exhaustion, which may facilitate the development of innovative therapeutic strategies in the field of cancer treatment.
Topics: Humans; Arginase; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Macrophages; Nanoparticles; Panax; T-Cell Exhaustion; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 38012650
DOI: 10.1186/s13046-023-02888-7 -
The Journal of Clinical Investigation Apr 2022The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the...
The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.
Topics: Animals; Breast Neoplasms; Female; Fibroblasts; Humans; Mice; Oncostatin M; Signal Transduction; Tumor Microenvironment
PubMed: 35192545
DOI: 10.1172/JCI148667