Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354812 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic alterations that are critical for cancer cell growth and metastasis are one of the key hallmarks of cancer. Here, we show that thymidine kinase 1 (TK1) is significantly overexpressed in tumor samples from lung adenocarcinoma (LUAD) patients relative to normal controls, and this TK1 overexpression is associated with significantly reduced overall survival and cancer recurrence. Genetic knockdown of TK1 with short hairpin RNAs (shRNAs) inhibits both the growth and metastatic attributes of LUAD cells in culture and in mice. We further show that transcriptional overexpression of TK1 in LUAD cells is driven, in part, by MAP kinase pathway in a transcription factor MAZ dependent manner. Using targeted and gene expression profiling-based approaches, we then show that loss of TK1 in LUAD cells results in reduced Rho GTPase activity and reduced expression of growth and differentiation factor 15 (GDF15). Furthermore, ectopic expression of GDF15 can partially rescue TK1 knockdown-induced LUAD growth and metastasis inhibition, confirming its important role as a downstream mediator of TK1 function in LUAD. Collectively, our findings demonstrate that TK1 facilitates LUAD tumor and metastatic growth and represents a target for LUAD therapy.
2019-09-23 | GSE90483 | GEO
Project description:Growth Differentiation Factor 15 (GDF15) is a divergent member of the TGF-β superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine BPD models, and GDF15 loss exacerbates oxidative stress and decreases viability in vitro in pulmonary epithelial and endothelial cells. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15-/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% O2) for 5 days after birth. The mice were euthanized on PND 21. Gdf15 -/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Upon exposure to hyperoxia, female mice had higher alveolar simplification in the Gdf15-/- group than the female WT group. Gdf15-/- and WT mice showed no difference in the degree of the arrest in angiogenesis upon exposure to hyperoxia. Gdf15-/- mice showed lower macrophage count in the lungs compared to WT mice. Our results suggest that Gdf15 deficiency decreases the tolerance to hyperoxic lung injury with evidence of sex-specific differences.
2023-07-20 | GSE211744 | GEO
Project description:Rationale: Growth/differentiation factor 15 (GDF15) is a stress cytokine with numerous proposed roles including stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the sources and downstream effects of GDF15 during pathogen-mediated injury remain unclear. Methods: We quantified GDF15 in plasma and lower respiratory tract (LRT) biospecimens from critically-ill humans with acute respiratory failure. Publicly available data from SARS-CoV-2 infection were re-analyzed. We utilized mouse models of acute lung injury mediated by P. aeruginosa exoproducts in wildtype mice and in mice genetically deficient for Gdf15 and its putative receptor, Gfral.Results: Plasma levels of GDF15 associated with worse outcomes and LRT GDF15 levels in critically-ill humans. Intra-tracheal P. aeruginosa Type 2 secretion system exoproducts (PA SN) were sufficient to induce airspace and plasma release of GDF15 in wildtype mice, which was attenuated during epithelial-specific Gdf15 deficiency. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium. Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and altered lung transcriptional profile during PA SN injury, which was not recapitulated in mice deficient for Gfral. Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but did increase circulating erythrocyte counts.Conclusions: Lung epithelium releases GDF15 during pathogen injury, which associates with plasma levels in both humans and mice and can increase erythrocyte counts in mice. Potential local and other extra-pulmonary roles for GDF15 remain undefined.
2024-02-08 | GSE253234 | GEO
Project description:Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after cancer drug treatment. These cells are the living proof of response to a drug, and an interesting experimental subject for biomarker discovery. Here, we performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. First, we showed that eribulin induces a specific secretome in DTP cells as compared to other microtubule targeting agents. Then, we selected and functionally validated growth differentiation factor 15 (GDF15) as a protein significantly over-secreted upon eribulin treatment. Interestingly, GDF15 expression is low/absent in cells that are sensitive to eribulin, strongly upregulated during the response to the drug, and downregulated when stable resistance is ultimately established. Proteomic results were confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. Unexpectedly, despite its biomarker potential for eribulin response, we found that GDF15 is also paradoxically required for survival of DTP cells, although once full resistance to eribulin is established, GDF15 expression largely disappears. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function conditions. These results pointed to a potential benefit of simultaneous targeting of GDF15/GFRAL and eribulin, and indeed we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired eribulin resistance, and possibly other cytotoxic drugs. Overall, the combination of cytotoxic agents with targeted agents aimed specifically at DTP cells could be an effective therapeutic approach for metastatic breast cancer patients.
2023-01-09 | PXD034037 | Pride
Project description:Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
2024-07-30 | E-MTAB-12831 | biostudies-arrayexpress
Project description:Elevation of growth differentiation factor 15 (GDF15) has recently emerged as a key driver of cancer cachexia, a syndrome of extreme weight loss that affects patients with various types of cancer. Chemotherapy, as well as the tumour itself have been reported to contribute to increased GDF15 secretion in both cancer and host tissues. Bromodomain and extraterminal (BET) domain proteins have been shown to regulate GDF15 expression in pancreatic cancer cells. With currently neither preventive strategies nor specific therapeutic options for cachexia available, antibodies targeting GDF15 or its receptor are being developed. However, the mechanism of chemotherapy-induced GDF15 upregulation in tumour and host cells is still unknown, leaving uncertainty about safety and efficacy of therapies targeting retrospective reduction of GDF15 in cancer cachexia. We tested various cardiotoxic drugs for their effect on GDF15 regulation in cardiomyocyte cell culture and analysed gene expression, mutational status, and pathway activities of the NCI-60 cancer cell line panels to get further insights into the regulation of GDF15 expression in both cancer and host cells upon treatment with anticancer drugs. To investigate the regulatory effect of BET inhibition on GDF expression more extensively, we screened BET inhibitors in doxorubicin treated human cardiomyocyte cell culture as well as in 21 cancer cell lines and performed differential analysis of gene expression, metabolites, and pathway activities. Our results reveal that DNA interacting compounds induce GDF15 expression in human cardiomyocytes up to 20-fold, whereas cardiotoxic drugs with other modes of action led, if at all, to less than 3-fold induction. We discovered that BET inhibitors suppress doxorubicin-induced GDF15 overexpression in human cardiomyocytes up to 7.4-fold (p=0.0051). In cancer cell lines, we identified compound-specific gene signatures that correlate with the extent of GDF15 induction upon treatment in the espective cell line. BET inhibition also reduces GDF15 expression in a defined subset of cancer cell lines that differentiate from the other tested cell lines in a less active PI3K/Akt axis and significantly higher extracellular pantothenate concentration (p=0.00095). We identified compound- and cell-line-specific gene signatures that predict GDF15 upregulation upon treatment, providing indication that the risk for drug-induced GDF15 overexpression and concomitant cachexia can be reduced by a biomarker-driven selection of patient-specific anticancer agents. Our results suggest that BET inhibitors could counteract cachexia at the transcriptional level in tumour and host tissues by reducing GDF15 expression. We identified characteristic gene and metabolite expressions of responsive cancer cell lines that can serve as biomarkers for patient selection.
2023-07-07 | GSE210540 | GEO
Project description:Elevation of growth differentiation factor 15 (GDF15) has recently emerged as a key driver of cancer cachexia, a syndrome of extreme weight loss that affects patients with various types of cancer. Chemotherapy, as well as the tumour itself have been reported to contribute to increased GDF15 secretion in both cancer and host tissues. Bromodomain and extraterminal (BET) domain proteins have been shown to regulate GDF15 expression in pancreatic cancer cells. With currently neither preventive strategies nor specific therapeutic options for cachexia available, antibodies targeting GDF15 or its receptor are being developed. However, the mechanism of chemotherapy-induced GDF15 upregulation in tumour and host cells is still unknown, leaving uncertainty about safety and efficacy of therapies targeting retrospective reduction of GDF15 in cancer cachexia. We tested various cardiotoxic drugs for their effect on GDF15 regulation in cardiomyocyte cell culture and analysed gene expression, mutational status, and pathway activities of the NCI-60 cancer cell line panels to get further insights into the regulation of GDF15 expression in both cancer and host cells upon treatment with anticancer drugs. To investigate the regulatory effect of BET inhibition on GDF expression more extensively, we screened BET inhibitors in doxorubicin treated human cardiomyocyte cell culture as well as in 21 cancer cell lines and performed differential analysis of gene expression, metabolites, and pathway activities. Our results reveal that DNA interacting compounds induce GDF15 expression in human cardiomyocytes up to 20-fold, whereas cardiotoxic drugs with other modes of action led, if at all, to less than 3-fold induction. We discovered that BET inhibitors suppress doxorubicin-induced GDF15 overexpression in human cardiomyocytes up to 7.4-fold (p=0.0051). In cancer cell lines, we identified compound-specific gene signatures that correlate with the extent of GDF15 induction upon treatment in the espective cell line. BET inhibition also reduces GDF15 expression in a defined subset of cancer cell lines that differentiate from the other tested cell lines in a less active PI3K/Akt axis and significantly higher extracellular pantothenate concentration (p=0.00095). We identified compound- and cell-line-specific gene signatures that predict GDF15 upregulation upon treatment, providing indication that the risk for drug-induced GDF15 overexpression and concomitant cachexia can be reduced by a biomarker-driven selection of patient-specific anticancer agents. Our results suggest that BET inhibitors could counteract cachexia at the transcriptional level in tumour and host tissues by reducing GDF15 expression. We identified characteristic gene and metabolite expressions of responsive cancer cell lines that can serve as biomarkers for patient selection.
2023-07-07 | GSE210541 | GEO
Project description:Characterizing signal pathway alterations that contribute to cellular transformation induced by loss of Fhit protein Abstract: The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single‐base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome “caretaker” whose loss initiates genome instability in preneoplastic lesions. To follow the early genetic alterations and functional changes induced by Fhit loss that may recapitulate the neoplastic process in vitro, we established epithelial cell lines from kidney tissues of Fhit−/− and +/+ mouse pups early after weaning, and subjected cell cultures to nutritional and carcinogen stress, which +/+ cells did not survive. Through transcriptome profiling and protein expression analysis, we observed changes in the Trp53/p21 and survivin apoptotic pathways in −/− cells, and in expression of proteins involved in epithelial–mesenchymal transition. Some Fhit‐deficient cell lines showed anchorage‐independent colony formation and increased invasive capacity in vitro. Furthermore, cells of stressed Fhit−/− cell lines formed s.c. and metastatic tumors in nude mice. Collectively, we show that Fhit loss and subsequent thymidine kinase 1 inactivation, combined with selective pressures, leads to neoplasia‐associated alterations in genes and gene expression patterns in vitro and in vivo.
2019-07-19 | GSE134478 | GEO
Project description:Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging4-8. Our new data identifies Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling efficient metastatic outgrowth. Further, we have identified the tyrosine kinase receptors AXL and MER as promoting a dormancy-toreactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung.
2022-03-03 | MSV000088977 | MassIVE
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest and most metastatic cancers in human. PDACs respond poorly to therapies, partly due to cancer stem cells (CSCs) that self-renew, survive chemotherapies, metastasise and replenish the tumour. Factors secreted by tumour cells mediate autocrine/paracrine crosstalk with surrounding cells contributing to the stem cell niche but are still insufficiently characterised. Here we used quantitative SILAC proteomics to identify secreted factors enriched in CSC secretome compared to non-CSCs. Among them were GDF15 and VGF, factors involved in cachexia and pain stimuli. GDF15 and VGF promoted CSC self-renewal and growth through autocrine effects. TGFβ/Activin signalling lowered GDF15 and VGF expression via SMAD2/3-SMAD4-SNON, switching to ATF4-CREB-mediated induction upon cell stress. Co-culture of PDAC-CSCs and hESC-derived neural cells for mimicking cellular crosstalk in PDAC revealed that paracrine signalling via GDF15/VGF promoted nociceptor formation and neurite outgrowth. In turn, Substance P from neurons supported CSC self-renewal, EMT/migration and clonal evolution that was also impacted by SMAD4 genetic status. Lastly, the serum levels of GDF15 and VGF were elevated in PDAC patients suggesting their utility as biomarkers for PDAC detection. Collectively, our data uncovered that cachexia and pain signalling factors mediate the crosstalk between CSCs and nociceptors.
2024-04-06 | PXD046026 | Pride