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Oncometabolic nuclear reprogramming of cancer stemness

ABSTRACT: By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modelling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the “energy barriers” separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish for the first time the concept of oncometabolic nuclear reprogramming of stemness as a novel metabolo-epigenetic mechanism for generation of cancer stem-like cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76263 | GEO | 2016/04/08

SECONDARY ACCESSION(S): PRJNA306745

REPOSITORIES: GEO

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Homo sapiens

Project description:Oncometabolic nuclear reprogramming of cancer stemness

| PRJNA306745 | ENA

Autophagy mediates temporary reprogramming and dedifferentiation in plant somatic cells

Project description:Somatic cells acclimate to changes in the environment by temporary reprogramming. Much has been learned about transcription factors that induce these cell-state switches in both plants and animals, but how cells rapidly modulate their proteome remains elusive. Here, we show rapid induction of autophagy during temporary reprogramming in plants triggered by phytohormones, immune and danger signals. Quantitative proteomics following sequential reprogramming revealed that autophagy is required for timely decay of previous cellular states and for tweaking the proteome to acclimate to the new conditions. Signatures of previous cellular programs thus persist in autophagy deficient cells, affecting cellular decision-making. Concordantly, autophagy deficient cells fail to acclimatize to dynamic climate changes. Similarly, they have defects in dedifferentiating into pluripotent stem cells, and redifferentiation during organogenesis. These observations indicate that autophagy mediates cell state switches that underlie somatic cell reprogramming in plants and possibly other organisms, and thereby promotes phenotypic plasticity.

2019-12-04 | PXD016575 | Pride

Nuclear and cytosolic fractions of SOX2 synergise as transcriptional and translational co-regulators of cell fate

Project description:Stemness depends on a series of specific transcription regulators that suppress default differentiation and/or promote self-renewal. A prominent example thereof is SOX2 (SRY homology Box 2), a protein that further contributes to pluripotency and the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Here we uncover that SOX2 exerts these functions not only via transcriptional roles, but also by directly regulating translation. We show that SOX2 associates with ribosomal 40S subunits in the cytoplasm to alter the protein expression of signaling factors and metabolic components pivotal for stemness. Specifically, a low complexity region in the C-terminal part of SOX2 that interacts with the ribosome to modulate protein synthesis, is identified as critically required for SOX2-induced clonogenicity in human cancer cells and the reprogramming of fibroblasts to iPSCs. Mechanistically, SOX2 translationally enforces insulin/PI3K signaling while suppressing the formation of acetyl CoA synthetase 2 (ACSS2) protein, a driver of acetate consuming cell differentiation. Expression of either full-length SOX2 or its C-terminus only increases glucose consumption and acidification in cultured human cancer cells, thereby promoting clonogenicity. In the absence of SOX2 expression, ACSS2 knockdown or supplementation with acetate provide a partial rescue. Together, these data indicate novel ribosome-based mechanistic contributions of pluripotency factors to stemness and cell fate determination.

2024-09-16 | PXD015157 | Pride

RASSF1A controls Tissue Stiffness and Cancer Stem-like Cells in Lung Adenocarcinoma

Project description:Lung cancer remains the leading cause of cancer-related death due to poor treatment responses and resistance arising from tumor heterogeneity. Here we show that adverse prognosis associated with epigenetic silencing of the tumour suppressor RASSF1A is due to increased deposition of extracellular matrix (ECM), tumour stiffness and metastatic dissemination in vitro and in vivo. We find that lung cancer cells with RASSF1A promoter methylation display constitutive nuclear YAP1 and expression of collagen prolylhydroxylase (P4HA2) which increases collagen deposition. Furthermore, we identify that elevated collagen creates a stiff-ECM which in turn triggers cancer stem-like programming and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverse these effects and increase markers of lung differentiation (TTF-1, Mucin5B). Our study identifies RASSF1A as a clinical biomarker associated with mechanical properties of ECM which increases levels of cancer stemness and risk of metastatic progression in lung adenocarcinoma. Moreover, we highlight P4HA2 as a potential target for uncoupling ECM signals that support cancer stemness.

2019-05-20 | PXD012694 | Pride

The E3 ubiquitin ligase function of the epigenetic reader PHF16 is crucial for injury-induced intestinal regeneration

Project description:The intestine has a remarkable capacity to regenerate during homeostasis by the vigorous intestinal stem cells (ISCs) that reside in the base of the crypts. ISCs are easily impaired by DNA damage due to their active cell cycle. Intriguingly, certain cell populations possess the dedifferentiating ability to restore ISCs after ablation, although the molecular mechanisms by which these cells dedifferentiate into ISCs are largely unknown. Here, we performed single-cell RNA-seq using wild type and Phf16 knockout mice from normal or after irradiation to elucidate molecular mechanisms of Phf16 in intestinal regeneration. Our work characterizes that Phf16 is crucial for downregulating stemness in revival stem cells.

2024-07-24 | GSE235780 | GEO

Quantitative Proteomics Reveals Metabolic Differences in Homing and Non-Homing Glioma Stem Cell Xenografts and Stromal Cells

Project description:Glioblastoma is the most common and most devastating adult primary brain tumor. Despite aggressive multimodal therapy, the median survival is approximately one year after diagnosis. In recent years bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have shown promise as cell-based delivery vehicles for anti-glioma therapeutics. This is largely due to their innate ability to migrate towards gliomas. Several studies have successfully demonstrated their use as delivery vehicles for anti-glioma agents. However, it is now evident that BM-hMSCs demonstrate variable tropism towards gliomas based on a clinically relevant glioma stem cell (GSC) model of GBM. In this study, we compared the proteomic profile of cancer and stromal cell populations in GSC xenografts that attract BM-hMSCs (‘attractors’) with those to do not (‘non-attractors’) in order to identify cell-signaling pathways that may modulate BM-hMSCs homing followed by targeted transcriptomic analysis of human gene sets related to glioma biology. We identified lower protein expression of fatty acid metabolism and glucose-dependent metabolic pathways in attractors. While transcriptomic analysis suggested that N-linked glycosylation was increased. Conversely, glucose metabolic pathways, including oxidative phosphorylation, were increased in the stromal cells present in attractors. The results presented here provide the first evidence for glucose metabolism, reactive oxidative species and lipid-mediated tumor inflammatory response, and N-linked glycosylation in the homing of BM-hMSC to GSC xenografts. Reciprocal expression of these pathways in the stromal cell population may suggest microenvironment cross-talk. Our studies provide new insights on the signaling correlates underlying the differential homing capacity of BM-hMSCs to GSC xenografts.

2016-02-17 | PXD001778 | Pride

Extracellular-acidosis restricts one-carbon metabolism and preserves T cell stemness

Project description:The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness.

2023-01-17 | MTBLS6661 | MetaboLights

KK-LC-1 as a feasible therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer

Project description:Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromised the Hippo pathway and led to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identified the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employed a novel computational approach and discovered Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppressed TNBC tumor growth via a mechanism that reactivated the Hippo pathway and decreased TNBC ALDH+ cell stemness and viability.

2023-04-12 | PXD040200 | Pride

Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cells [scRNA-seq]

Project description:Coordinated regulation of stemness gene activity by transcriptional and translational controls poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of stemness gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC (FruC) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes stemness gene transcription in stem cells, a mechanism likely conserved from flies to humans.

2023-06-23 | GSE218255 | GEO

Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cells [CUT&Tag]

2023-06-23 | GSE218253 | GEO

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