The bone microenvironment invigorates metastatic seeds for further dissemination.

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.

GLUT and HK: Two primary and essential key players in tumor glycolysis.

Cancer cells reprogram their metabolism to become "glycolysis-dominant," which enables them to meet their energy and macromolecule needs and enhancing their rate of survival. This glycolytic-dominancy is known as the "Warburg effect", a significant factor in the growth and invasion of malignant tumors. Many studies confirmed that members of the GLUT family, specifically HK-II from the HK family play a pivotal role in the Warburg effect, and are closely associated with glucose transportation followed by glucose metabolism in cancer cells. Overexpression of GLUTs and HK-II correlates with aggressive tumor behaviour and tumor microenvironment making them attractive therapeutic targets. Several studies have proven that the regulation of GLUTs and HK-II expression improves the treatment outcome for various tumors. Therefore, small molecule inhibitors targeting GLUT and HK-II show promise in sensitizing cancer cells to treatment, either alone or in combination with existing therapies including chemotherapy, radiotherapy, immunotherapy, and photodynamic therapy. Despite existing therapies, viable methods to target the glycolysis of cancer cells are currently lacking to increase the effectiveness of cancer treatment. This review explores the current understanding of GLUT and HK-II in cancer metabolism, recent inhibitor developments, and strategies for future drug development, offering insights into improving cancer treatment efficacy.

Wheat TaNACα18 functions as a positive regulator of high-temperature adaptive responses and improves cell defense machinery.

Global wheat production amounted to >780 MMT during 2022-2023 whose market size are valued at >$128 billion. Wheat is highly susceptible to high-temperature stress (HTS) throughout the life cycle and its yield declines 5-7% with the rise in each degree of temperature. Previously, we reported an array of HTS-response markers from a resilient wheat cv. Unnat Halna and described their putative role in heat acclimation. To complement our previous results and identify the key determinants of thermotolerance, here we examined the cytoplasmic proteome of a sensitive cv. PBW343. The HTS-triggered metabolite reprograming highlighted how proteostasis defects influence the formation of an integrated stress-adaptive response. The proteomic analysis identified several promising HTS-responsive proteins, including a NACα18 protein, designated TaNACα18, whose role in thermotolerance remains unknown. Dual localization of TaNACα18 suggests its crucial functions in the cytoplasm and nucleus. The homodimerization of TaNACα18 anticipated its function as a transcriptional coactivator. The complementation of TaNACα18 in yeast and overexpression in wheat demonstrated its role in thermotolerance across the kingdom. Altogether, our results suggest that TaNACα18 imparts tolerance through tight regulation of gene expression, cell wall remodeling and activation of cell defense responses.

Transcriptomic profiling reveals the complex interaction between a bipartite begomovirus and a cucurbitaceous host plant.

BACKGROUND: Begomoviruses are major constraint in the production of many crops. Upon infection, begomoviruses may substantially modulate plant biological processes. While how monopartite begomoviruses interact with their plant hosts has been investigated extensively, bipartite begomoviruses-plant interactions are understudied. Moreover, as one of the major groups of hosts, cucurbitaceous plants have been seldom examined in the interaction with begomoviruses. RESULTS: We profiled the zucchini transcriptomic changes induced by a bipartite begomovirus squash leaf curl China virus (SLCCNV). We identified 2275 differentially-expressed genes (DEGs), of which 1310 were upregulated and 965 were downregulated. KEGG enrichment analysis of the DEGs revealed that many pathways related to primary and secondary metabolisms were enriched. qRT-PCR verified the transcriptional changes of twelve selected DEGs induced by SLCCNV infection. Close examination revealed that the expression levels of all the DEGs of the pathway Photosynthesis were downregulated upon SLCCNV infection. Most DEGs in the pathway Plant-pathogen interaction were upregulated, including some positive regulators of plant defenses. Moreover, the majority of DEGs in the MAPK signaling pathway-plant were upregulated. CONCLUSION: Our findings indicates that SLCCNV actively interact with its cucurbitaceous plant host by suppressing the conversion of light energy to chemical energy and inducing immune responses. Our study not only provides new insights into the interactions between begomoviruses and host plants, but also adds to our knowledge on virus-plant interactions in general.

Cardiac reprogramming reduces inflammatory macrophages and improves cardiac function in chronic myocardial infarction.

Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI.

Aspirin loaded extracellular vesicles inhibit inflammation of macrophages via switching metabolic phenotype in periodontitis.

OBJECTIVES: Changes of macrophage in the local immune microenvironment of periodontitis cause alveolar bone resorption. This study aims to investigate the effect of a new drug delivery method of aspirin on the immune microenvironment of periodontitis to promote alveolar bone repair, and to explore mechanism of aspirin's effect on macrophage. METHODS: We isolated extracellular vesicles (EVs) from periodontal stem cells (PDLSCs) and loaded with aspirin by sonication, and then evaluated the treatment efficacy of aspirin-loaded vesicles (EVs-ASP) in periodontitis model in mice. In vitro, we explored the role of EVs-ASP in the regulation of LPS-induced macrophages. The underlying mechanism by which EVs-ASP regulates phenotypic remodeling of macrophages in periodontitis was further investigated. RESULTS: EVs-ASP inhibited the inflammatory environment of LPS-induced macrophage, and promoted anti-inflammatory macrophages formation both in vivo and in vitro, and reduced bone loss in periodontitis models. Moreover, EVs-ASP enhanced oxidative phosphorylation and suppressed glycolysis in macrophages. CONCLUSIONS: Consequently, EVs-ASP improves the periodontal immune microenvironment by enhancing oxidative phosphorylation (OXPHOS) in macrophages, resulting in a certain degree of regeneration of alveolar bone height. Our study provides a new potential strategy for bone repair in periodontitis therapy.

Suppression of the target of rapamycin kinase accelerates tomato fruit ripening through reprogramming the transcription profile and promoting ethylene biosynthesis.

Tomato fruit ripening is a unique process of nutritional and energy metabolism. Target of rapamycin (TOR), a conserved serine/threonine protein kinase in eukaryotes, controls cell growth and metabolism by integrating nutrient, energy, and hormone signals. However, it remains unclear whether TOR participates in the modulation of tomato fruit ripening. Here, we showed that the manipulation of SlTOR by chemical or genetic methods greatly alters the process of tomato fruit maturation. Expression pattern analysis revealed that the transcripts of SlTOR declined as fruit ripening progressed. Moreover, suppression of SlTOR by TOR inhibitor AZD8055 or knock down of its transcripts by inducible RNA interference, accelerated fruit ripening, and led to overall effects on fruit maturity, including changes in colour and metabolism, fruit softening, and expression of ripening-related genes. Genome-wide transcription analysis indicated that silencing SlTOR reprogrammed the transcript profile associated with ripening, including cell wall and phytohormone pathways, elevated the expression of ethylene biosynthetic genes, and further promoted ethylene production. In contrast, the ethylene action inhibitor 1-MCP efficiently blocked fruit maturation, even following SlTOR inhibition. These results suggest that accelerated fruit ripening caused by SlTOR inhibition depends on ethylene, and that SlTOR may function as a regulator in ethylene metabolism.

Imaging the metabolic reprograming of fatty acid synthesis pathway enables new diagnostic and therapeutic opportunity for breast cancer.

BACKGROUND: Reprogrammed metabolic network is a key hallmark of cancer. Profiling cancer metabolic alterations with spatial signatures not only provides clues for understanding cancer biochemical heterogeneity, but also helps to decipher the possible roles of metabolic reprogramming in cancer development. METHODS: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique was used to characterize the expressions of fatty acids in breast cancer tissues. Specific immunofluorescence staining was further carried out to investigate the expressions of fatty acid synthesis-related enzymes. RESULTS: The distributions of 23 fatty acids in breast cancer tissues have been mapped, and the levels of most fatty acids in cancer tissues are significantly higher than those in adjacent normal tissues. Two metabolic enzymes, fatty acid synthase (FASN) and acetyl CoA carboxylase (ACC), which being involved in the de novo synthesis of fatty acid were found to be up-regulated in breast cancer. Targeting the up-regulation of FASN and ACC is an effective approach to limiting the growth, proliferation, and metastasis of breast cancer cells. CONCLUSIONS: These spatially resolved findings enhance our understanding of cancer metabolic reprogramming and give an insight into the exploration of metabolic vulnerabilities for better cancer treatment.

PGAM5 deacetylation mediated by SIRT2 facilitates lipid metabolism and liver cancer proliferation.

Tumor metabolic reprogramming and epigenetic modification work together to promote tumorigenesis and development. Protein lysine acetylation, which affects a variety of biological functions of proteins, plays an important role under physiological and pathological conditions. Here, through immunoprecipitation and mass spectrum data, we show that phosphoglycerate mutase 5 (PGAM5) deacetylation enhances malic enzyme 1 (ME1) metabolic enzyme activity to promote lipid synthesis and proliferation of liver cancer cells. Mechanistically, we demonstrate that the deacetylase SIRT2 mediates PGAM5 deacetylation to activate ME1 activity, leading to ME1 dephosphorylation, subsequent lipid accumulation and the proliferation of liver cancer cells. Taken together, our study establishes an important role for the SIRT2-PGAM5-ME1 axis in the proliferation of liver cancer cells, suggesting a potential innovative cancer therapy.

Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells.

Transcription factor-mediated reprograming is a powerful method to study cell fate changes. In this study, we demonstrate that the transcription factor Gata6 can initiate reprograming of multiple cell types to induced extraembryonic endoderm stem (iXEN) cells. Intriguingly, Gata6 is sufficient to drive iXEN cells from mouse pluripotent cells and differentiated neural cells. Furthermore, GATA6 induction in human embryonic stem (hES) cells also down-regulates pluripotency gene expression and up-regulates extraembryonic endoderm (ExEn) genes, revealing a conserved function in mediating this cell fate switch. Profiling transcriptional changes following Gata6 induction in mES cells reveals step-wise pluripotency factor disengagement, with initial repression of Nanog and Esrrb, then Sox2, and finally Oct4, alongside step-wise activation of ExEn genes. Chromatin immunoprecipitation and subsequent high-throughput sequencing analysis shows Gata6 enrichment near pluripotency and endoderm genes, suggesting that Gata6 functions as both a direct repressor and activator. Together, this demonstrates that Gata6 is a versatile and potent reprograming factor that can act alone to drive a cell fate switch from diverse cell types.

The Role of Krüppel-like Factors in Pancreatic Physiology and Pathophysiology.

Krüppel-like factors (KLFs) belong to the family of transcription factors with three highly conserved zinc finger domains in the C-terminus. They regulate homeostasis, development, and disease progression in many tissues. It has been shown that KLFs play an essential role in the endocrine and exocrine compartments of the pancreas. They are necessary to maintain glucose homeostasis and have been implicated in the development of diabetes. Furthermore, they can be a vital tool in enabling pancreas regeneration and disease modeling. Finally, the KLF family contains proteins that act as tumor suppressors and oncogenes. A subset of members has a biphasic function, being upregulated in the early stages of oncogenesis and stimulating its progression and downregulated in the late stages to allow for tumor dissemination. Here, we describe KLFs' function in pancreatic physiology and pathophysiology.

Metabolic reprograming of MDSCs within tumor microenvironment and targeting for cancer immunotherapy.

A number of emerging studies in field of immune metabolism have indicated that cellular metabolic reprograming serves as a major administrator in maintaining the viability and functions of both tumor cells and immune cells. As one of the most important immunosuppressive cells in tumor stroma, myeloid-derived suppressor cells (MDSCs) dynamically orchestrate their metabolic pathways in response to the complicated tumor microenvironment (TME), a process that consequently limits the therapeutic effectiveness of anti-cancer treatment modalities. In this context, the metabolic vulnerabilities of MDSCs could be exploited as a novel immune metabolic checkpoint upon which to intervene for promoting the efficacy of immunotherapy. Here, we have discussed about recent studies highlighting the important roles of the metabolic reprograming and the core molecular pathways involved in tumor-infiltrating MDSCs. In addition, we have also summarized the state-of-the-art strategies that are currently being employed to target MDSC metabolism and improve the efficacy of antineoplastic immunotherapy.

The enduring effect of prenatal protein malnutrition on brain anatomy, physiology and behavior.

There is increasing evidence that the maternal environment exerts enduring influences on the fetal brain. In response to certain environmental stimuli such as reduced protein content, the fetus changes the course of its brain development, which leads to specific and programed changes in brain anatomy and physiology. These alterations produce a brain with a fundamentally altered organization, which then translates to alterations in adult cognitive function. The effects on brain and behavior may be linked, such that a prenatal stimulus relays a signal to alter brain development and encourage the selection and development of brain circuits and behaviors that would be beneficial for the environment in which the animal was anticipated to emerge. At the same time, the signal would deselect behaviors unlikely to be adaptive. We draw on evidence from rodent models to suggest that the brain that develops after a reduction in protein during the prenatal phase is not uniformly dysfunctional, but simply different. This perspective has implications for the role of prenatal factors in the production and expression of behavior, and may account for the elevation of risk factors for neurological and psychiatric illnesses.

Dynamic Distribution of HIG2A between the Mitochondria and the Nucleus in Response to Hypoxia and Oxidative Stress.

Mitochondrial respiratory supercomplex formation requires HIG2A protein, which also has been associated with cell proliferation and cell survival under hypoxia. HIG2A protein localizes in mitochondria and nucleus. DNA methylation and mRNA expression of the HIGD2A gene show significant alterations in several cancers, suggesting a role for HIG2A in cancer biology. The present work aims to understand the dynamics of the HIG2A subcellular localization under cellular stress. We found that HIG2A protein levels increase under oxidative stress. H2O2 shifts HIG2A localization to the mitochondria, while rotenone shifts it to the nucleus. HIG2A protein colocalized at a higher level in the nucleus concerning the mitochondrial network under normoxia and hypoxia (2% O2). Hypoxia (2% O2) significantly increases HIG2A nuclear colocalization in C2C12 cells. In HEK293 cells, chemical hypoxia with CoCl2 (>1% O2) and FCCP mitochondrial uncoupling, the HIG2A protein decreased its nuclear localization and shifted to the mitochondria. This suggests that the HIG2A distribution pattern between the mitochondria and the nucleus depends on stress and cell type. HIG2A protein expression levels increase under cellular stresses such as hypoxia and oxidative stress. Its dynamic distribution between mitochondria and the nucleus in response to stress factors suggests a new communication system between the mitochondria and the nucleus.

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), ß or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARß/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARß/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARß/δ to alleviate skin inflammation is discussed.

A Selection of Macrocyclic Peptides That Bind STING From an mRNA-Display Library With Split Degenerate Codons.

Recent improvements in mRNA display have enabled the selection of peptides that incorporate non-natural amino acids, thus expanding the chemical diversity of macrocycles beyond what is accessible in nature. Such libraries have incorporated non-natural amino acids at the expense of natural amino acids by reassigning their codons. Here we report an alternative approach to expanded amino-acid diversity that preserves all 19 natural amino acids (no methionine) and adds 6 non-natural amino acids, resulting in the highest sequence complexity reported to date. We have applied mRNA display to this 25-letter library to select functional macrocycles that bind human STING, a protein involved in immunoregulation. The resulting STING-binding peptides include a 9-mer macrocycle with a dissociation constant (KD ) of 3.4 nM, which blocks binding of cGAMP to STING and induces STING dimerization. This approach is generalizable to expanding the amino-acid alphabet in a library beyond 25 building blocks.

Heat Sensing and Lipid Reprograming as a Signaling Switch for Heat Stress Responses in Wheat.

Temperature is an essential physical factor that affects the plant life cycle. Almost all plant species have evolved a robust signal transduction system that enables them to sense changes in the surrounding temperature, relay this message and accordingly adjust their metabolism and cellular functions to avoid heat stress-related damage. Wheat (Triticum aestivum), being a cool-season crop, is very sensitive to heat stress. Any increase in the ambient temperature, especially at the reproductive and grain-filling stages, can cause a drastic loss in wheat yield. Heat stress causes lipid peroxidation due to oxidative stress, resulting in the damage of thylakoid membranes and the disruption of their function, which ultimately decreases photosynthesis and crop yield. The cell membrane/plasma membrane plays prominent roles as an interface system that perceives and translates the changes in environmental signals into intracellular responses. Thus, membrane lipid composition is a critical factor in heat stress tolerance or susceptibility in wheat. In this review, we elucidate the possible involvement of calcium influx as an early heat stress-responsive mechanism in wheat plants. In addition, the physiological implications underlying the changes in lipid metabolism under high-temperature stress in wheat and other plant species will be discussed. In-depth knowledge about wheat lipid reprograming can help develop heat-tolerant wheat varieties and provide approaches to solve the impact of global climate change.

The transcriptional reprograming and functional identification of WRKY family members in pepper's response to Phytophthora capsici infection.

BACKGROUND: Plant transcription factors (TFs) are key transcriptional regulators to manipulate the regulatory network of host immunity. However, the globally transcriptional reprogramming of plant TF families in response to pathogens, especially between the resistant and susceptible host plants, remains largely unknown. RESULTS: Here, we performed time-series RNA-seq from a resistant pepper line CM334 and a susceptible pepper line EC01 upon challenged with Phytophthora capsici, and enrichment analysis indicated that WRKY family most significantly enriched in both CM334 and EC01. Interestingly, we found that nearly half of the WRKY family members were significantly up-regulated, whereas none of them were down-regulated in the two lines. These induced WRKY genes were greatly overlapped between CM334 and EC01. More strikingly, most of these induced WRKY genes were expressed in time-order patterns, and could be mainly divided into three subgroups: early response (3 h-up), mid response (24 h-up) and mid-late response (ML-up) genes. Moreover, it was found that the responses of these ML-up genes were several hours delayed in EC01. Furthermore, a total of 19 induced WRKY genes were selected for functional identification by virus-induced gene silencing. The result revealed that silencing of CaWRKY03-6, CaWRKY03-7, CaWRKY06-5 or CaWRKY10-4 significantly increase the susceptibility to P. capsici both in CM334 and EC01, indicating that they might contribute to pepper's basal defense against P. capsici; while silencing of CaWRKY08-4 and CaWRKY01-10 significantly impaired the disease resistance in CM334 but not in EC01, suggesting that these two WRKY genes are prominent modulators specifically in the resistant pepper plants. CONCLUSIONS: These results considerably extend our understanding of WRKY gene family in pepper's resistance against P. capsici and provide potential applications for genetic improvement against phytophthora blight.

Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity.

Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid's role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.

Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6-deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down-regulation of one such target, c-Myc, relieves the differentiation block. Smg6-null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming.