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| Status |
Public on Jul 07, 2023 |
| Title |
GDF15 gene suppression by BET inhibition and gene signature based personalized chemotherapy to counteract cachexia [Quant-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Colon cancer cell lines were grown in media and treated with either DMSO (control) or compound. BI 894999 (WO2014076237) is the clinical compound synthesized by Boehringer Ingelheim. The experiment was performed in biological duplicates per condition/cell lines. Information about sampling time points, compounds, compound concentrations, and replicates are detailed out in the respective sample descriptions. All samples were subjected to RNA isolation, followed by library preparation (QuantSeq 3' mRNA-Seq Library Prep Kit FWD for Illumina, Lexogen), and messenger RNA sequencing on an Illumina NextSeq 500 system.
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| Contributor(s) |
Gerlach D, Tontsch-Grunt U, Norbert S |
| Citation(s) |
37495707 |
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| Submission date |
Aug 04, 2022 |
| Last update date |
Oct 09, 2023 |
| Contact name |
Daniel Gerlach |
| E-mail(s) |
daniel.gerlach@boehringer-ingelheim.com
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| Organization name |
Boehringer Ingelheim RCV GmbH & Co KG
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| Department |
Global Computational Biology and Digital Sciences
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| Street address |
Dr.-Boehringer-Gasse 5-11
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| City |
Vienna |
| ZIP/Postal code |
1121 |
| Country |
Austria |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (54)
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| This SubSeries is part of SuperSeries: |
| GSE210542 |
GDF15 gene suppression by BET inhibition and gene signature based personalized chemotherapy to counteract cachexia |
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| Relations |
| BioProject |
PRJNA866131 |
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