Ageing promotes metastasis via activation of the integrated stress response [RNA-Seq OE]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE289768 | GEO | 2026/01/23
REPOSITORIES: GEO
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Project description:Lung cancer predominantly affects older individuals, yet how physiological aging influences tumor evolution remains poorly understood. Here, we show that aging reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumor growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumor cells exhibit increased sensitivity to the PERK–eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signaling. Targeting the ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The aging–ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumors and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR–ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumors, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer
2026-01-23 | GSE263688 | GEO
Project description:Lung cancer predominantly affects older individuals, yet how physiological aging influences tumor evolution remains poorly understood. Here, we show that aging reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumor growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumor cells exhibit increased sensitivity to the PERK–eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signaling. Targeting the ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The aging–ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumors and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR–ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumors, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer
2026-01-23 | GSE263687 | GEO
Project description:Lung adenocarcinoma (LUAD) progresses from a single alveolar type 2 (AT2) cell to a complex, malignant tissue through a multi-step process involving acquisition of high plasticity and stem cell-like traits in a subset of cancer cells. Oncogenic transformation and signals from the tumor microenvironment (TME) activate the integrated stress response (ISR), a key survival mechanism that allows tumor cells to adapt and thrive under stress. Using single-cell transcriptomics, we identified high stemness and plasticity cell clusters in mouse LUAD tumors expressing mutant KRAS and lacking TP53 (KP model), which displayed elevated ISR program expression. Disrupting ISR via the genetic loss of phosphorylated eIF2a (p-eIF2a) or the transcription factor ATF4 hindered LUAD growth and the emergence of high-plasticity, stemness-associated lineages, resulting in the formation of a distinct cell state characterized by mitochondrial dysfunction. Additionally, treatment with ISRIB - a small-molecule ISR inhibitor with low toxicity and cognitive benefits - led to an accumulation of AT2-like LUAD cells, blocking developmental progression and tumorigenesis. In human LUAD, the ISR program is similarly elevated in KRAS-mutant tumors with high plasticity and stemness features and correlates with poor patient outcomes. These findings suggest that ISR is a key driver of LUAD progression and targeting ISR could provide a promising approach to slow LUAD progression and improve lung cancer treatment outcomes.
2026-01-01 | GSE287513 | GEO
Project description:The integrated stress response (ISR) is a conserved pathway which is activated by cells that are exposed to stress. In lung adenocarcinoma (LUAD), activation of the ATF4 branch of the ISR by particular oncogenic mutations has been linked to the regulation of amino acid metabolism. In the present study, we provide evidence for ATF4 activation across multiple stages and molecular subtypes of human LUAD. In response to extracellular amino acid limitation, LUAD cells with diverse genotypes broadly induce ATF4 in an eIF2α dependent manner, which can be blocked pharmacologically using the integrated stress response inhibitor (ISRIB). Although suppressing eIF2α or ATF4 can trigger different biological consequences, adaptive cell cycle progression and cell migration are particularly sensitive to inhibition of the ISR. These phenotypes specifically require the ATF4 target gene asparagine synthetase (ASNS), which maintains protein translation independently of the mTOR/PI3K pathway. Moreover, NRF2 protein levels and oxidative stress can be modulated by the ISR downstream of ASNS. Finally, we demonstrate that the ISR via ASNS controls the biosynthesis of select proteins, including the cell cycle regulator cyclin B1, which are associated with poor LUAD patient prognosis. Our findings uncover new regulatory layers of the ISR pathway and its control of proteostasis in lung cancer cells as they adapt to metabolic barriers during tumor progression.
2019-10-23 | GSE126232 | GEO
Project description:Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC). Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrate that organismal aging accelerates PDAC progression and metastasis. Through transcriptomic profiling, we identify a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. To directly test the functional impact of stromal aging, we employed heterochronic co-implantation models, revealing that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, fail to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, our work establishes a new conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, this work raises compelling questions about the underlying molecular mechanisms—questions now accessible through our model—and lays the foundation for future efforts to therapeutically target stromal aging in PDAC.
2026-01-12 | PXD068597 | Pride
Project description:Metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) is an essential mechanism of synaptic plasticity across various brain regions and is closely linked to numerous learning processes. Previous studies have demonstrated the interplay between mGluR-LTD and the phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), a key component of the integrated stress response (ISR) pathway. However, the role of activating transcription factor 4 (ATF4)—the primary downstream effector of the integrated stress response (ISR)—in the mechanisms underlying mGluR-LTD has not been thoroughly investigated. In this study, we examine the role of ATF4 in mGluR-LTD and identify several targets that show differential expression when the gene encoding ATF4 is deleted in excitatory neurons.
2026-02-05 | PXD066551 | Pride
Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPβ and CHOP were largely dispensable for induction of stress genes. Cebpgâ/â MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ/â mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ/â mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPγ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. Evaluation of genomic binding of 2 bZIP transcription factors under amino acid deprivation conditions in mouse embryonic fibroblasts
2015-11-19 | E-GEOD-75165 | biostudies-arrayexpress
Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPβ and CHOP were largely dispensable for induction of stress genes. Cebpgâ??/â?? MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ??/â?? mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ??/â?? mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPγ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. WT, Atf4-/-, and Cebpg-/- MEFs (passage 3) were cultured under normal and AAD conditions. RNA from each treatment condition was collected in triplicate for hybrization on Affymetrix Mouse Genome 430 2.0 microarrays.
2015-11-19 | E-GEOD-75150 | biostudies-arrayexpress
Project description:Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC). Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrate that organismal aging accelerates PDAC progression and metastasis. Through transcriptomic profiling, we identify a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. To directly test the functional impact of stromal aging, we employed heterochronic co-implantation models, revealing that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, fail to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, our work establishes a new conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, this work raises compelling questions about the underlying molecular mechanisms—questions now accessible through our models—and lays the foundation for future efforts to therapeutically target stromal aging in PDAC.
2025-11-20 | GSE298701 | GEO
Project description:Cells rapidly and extensively remodel their transcriptome in response to stress to restore homeostasis, but the underlying mechanisms are not fully understood. Here we characterize the dynamic changes in transcriptome, epigenetics, and 3D genome organization during the integrated stress response (ISR). ISR induction triggers widespread transcriptional changes within 6 hours, coinciding with increased binding of ATF4, a key transcriptional effector. Notably, ATF4 binds to hundreds of genes even under non-stress conditions, priming them for stronger activation upon stress. The transcriptional changes during ISR do not rely on increased H3K27 acetylation, chromatin accessibility, or rewired enhancer-promoter looping. Instead, ATF4-mediated gene activation is linked to the redistribution of CEBPγ from non-ATF4 sites to a subset of ATF4-bound regions, likely by forming an ATF4/CEBPγ heterodimer. CEBPγ preferentially targets the sites pre-occupied by ATF4, as well as genomic regions exhibiting a unique higher-order chromatin structure signature. Thus, the transcriptional responses during ISR are largely pre-wired by intrinsic chromatin properties. These findings provide novel insights into transcriptional remodeling during ISR with broader implications for other stress responses. Through the IP-MS experiments, we determined the proteins that interacted with ATF4 and their change during ISR.
2024-12-05 | PXD058631 |