Hypoxia induced ATF3 escalates breast cancer invasion by increasing collagen deposition
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ABSTRACT:
PROVIDER: PRJNA1148531 | ENA |
REPOSITORIES: ENA
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Project description:Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra- and/or intracellular changes. In this study, we observed that one of the ATFs Activating transcription factor 3 (ATF3) is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. Additionally, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion conducive extracellular matrix (ECM) under hypoxic condition. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. It is interesting to note that ATF3's involvement in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Further, we also show that the demethylated DNA region of intron 9a then becomes accessible to CTCF. Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA PolII pause via CTCF at the intron 9a leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results provide a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can be potentially exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion.
2024-12-31 | GSE274936 | GEO
Project description:Mutant collagen COL11A1 enhances cancerous invasion
| PRJNA743076 | ENA
Project description:Pathological fibrosis, an excessive accumulation of collagen, compromises tissue architecture, impedes its function and represents a medical complication. Properties of the amniotic membrane have demonstrated potential to regulate fibrotic processes. RNA sequencing analysis evaluated the effects of dehydrated human amnion/chorion membrane (DHACM) on fibrotic events using in vitro macromolecular crowding to mimic a physiologically relevant microenvironment. Functional enrichment with Reactome pathway analysis indicated that the function of a subset of these dysregulated genes was associated with the composition and function of the extracellular matrix. Further use of macromolecular crowding in vitro was used to evaluate the effects of DHACM and a lyophilized human amnion/chorion membrane (LHACM) on type 1 collagen production and deposition under profibrotic conditions (addition of TGFβ1). In the continued presence of TGFβ1, LHACM and DHACM regulated the intracellular production and extracellular deposition of type 1 collagen. In addition, results suggest that the effect on collagen deposition could in part be modulated through the regulation of proteins responsible for the extracellular post-translational modifications of collagen. These observations may support the use of DHACM and LHACM in the regulation collagen production/deposition in profibrotic environments.
2024-05-06 | GSE247237 | GEO
Project description:Mutant collagen COL11A1 enhances cancerous invasion [RNA-seq]
| PRJNA741266 | ENA
Project description:Human Amniotic membrane modulates collagen production and deposition in vitro
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Project description:Nf1 Deficiency Increases Mammary Collagen Deposition and Restricts Adipocyte Differentiation Before Tumor Formation
| PRJNA966987 | ENA
Project description:BACKGROUND: The NF1 tumor suppressor gene is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1) – a tumor predisposition syndrome caused by a germline NF1 mutation – have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanisms by which NF1 mutation leads to breast cancer tumorigenesis are not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. METHODS: To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development and develops highly penetrant breast cancer. RESULTS: We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient rat mammary mature adipocytes have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation but flow cytometry analysis did not show a change mammary adipose-derived mesenchymal stem cell abundance. CONCLUSION: Collectively, these studies uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary gland will create a foundation for developing early detection strategies of breast cancer among NF1 patients.
2023-05-08 | GSE231603 | GEO
Project description:Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven pro-inflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3-/- neutrophil recruitment to wild type lungs. In vitro, ATF3-/- neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3-/- neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3-/- and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production, but promotion of neutrophil chemotaxis. Ly6G+ neutrophils were purified by magnetic beads from WT or ATF3 KO bone marrow and RNA was immediately isolated for global gene expression using microarrays.
2014-04-05 | E-GEOD-53973 | biostudies-arrayexpress
Project description:Collagen, a critical component of the tumor microenvironment (TME), significantly influences cancer-associated fibrosis, tissue stiffness, immune response, and metastasis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive collagen deposition, and effective therapies remain limited. Our research challenges conventional understanding by highlighting the remarkable ability of specific tumor epithelial populations, particularly those with low levels of L1 cell adhesion molecule (L1CAM) expression (L1low), to actively modulate collagen dynamics within the TME. Transcriptome analysis of PDAC cells with varying L1 expression reveals shifts in collagen-related pathways, with heightened expression of collagen 17A1 (COL17A1) in L1low cells. Alongside, L1low cells exhibit enhanced migratory capacity. In an orthotopic mouse model, L1low cancer cells demonstrate increased collagen deposition, resistance to gemcitabine treatment, and an elevated propensity for liver metastases. Treatment with Tranilast, an anti-fibrotic drug, significantly reduces tumor volume and collagen deposition while enhancing L1 expression. This, in turn, mitigates tumor invasiveness and suppresses metastases formation. Overall, our study uncovers a novel role for L1CAM in PDAC aggressiveness and fibrosis, revealing a new epithelial population capable of collagen secretion and challenging the traditional notion that this function is solely attributed to stromal cells.
2024-06-11 | GSE268948 | GEO
Project description:Cancer-host interactions play an important role in cancer development. We identified ATF3, an adaptive-response gene, in the host to facilitate metastasis. We also demonstrated that the macrophage is one of the key cell types for host-ATF3 to function. Furthermore, matrix metalloproteases 9 is a functionally important target gene of ATF3 in co-culture assays. Gene profiling with bioinformatics analyses indicated that ATF3 downstream gene-signatures derived from tumor-associated macrophages in a mouse model can distinguish human tumor stroma from M-bM-^@M-^\distantM-bM-^@M-^] stroma in and can stratify the patients into high- versus low-risk groups. Importantly, multivariate analyses indicated that high expression of ATF3 itself in mononuclear cells within breast tumors is an independent predictor for breast cancer-specific death in a cohort of patients. Approximately 21 days after orthotopic injection of PyMT breast cancer cells into syngeneic C57BL/6 mice (WT or ATF3 KO hosts) tumors were removed (tumors were ~1 cm cubic in volume), enzymatically digested to generate single cell suspensions, stained, and sorted for F4/80 and CD45 double positive cells by FACS. Isolated cells were lysed in TRIzol, processed to generate total RNA, and gene expression analyzed by microarray. Four replicate WT TAM samples and four replicate ATF3 KO TAM samples were analyzed.
2013-07-10 | E-GEOD-36904 | biostudies-arrayexpress