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| Status |
Public on Nov 16, 2024 |
| Title |
Microbial metabolite ammonia disrupts CEACAM1-TGF-β signaling to promote colon cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Colorectal cancer (CRC) incidence is rising globally and anticipated to become the leading cause of cancer death in younger individuals. Potential risk factors are diet induced obesity and altered microbiomes that lead to accumulation of toxic metabolite accumulation. However, how ammonia and other microbial metabolites impact key signaling pathways, such as TGF-β signaling, to promote CRC remains unclear. Our study investigates a critical link between gut microbiome alterations, ammonia, and their toxic effects on the TGF-β signaling pathway, to drive CRC progression. We found that in an obesity induced mouse model of cancer, altered microbial populations and ammonia promote Caspase-3-mediated cleavage of SMAD3 adaptor βII-spectrin (SPTBN1). Cleaved SPTBN1 fragments form adducts with ammonia to induce pro-inflammatory cytokine expression and alter TGF-β signaling driving CRC. Extending on Alphafold docking simulations, we identified that ammonia interacts with six polar residues at SPTBN1 (S553, Y556, S663, Y666, N986, and T1178) of cleaved SPTBN1 fragments to form hydrogen bonds that disrupt downstream SMAD3 signaling, altering TGF-β signaling to a protumorigenic phenotype. Blocking SPTBN1, through an SPTBN1 specific siRNA blocks ammonia toxicity and restore TGF-β signaling by reducing the abundance of SPTBN1 cleaved fragments. Importantly, SPTBN1 siRNA blocks ammonia toxicity and restore normal TGF-β signaling in CRC cells. Moreover, our research establishes crosstalk between TGF-β signaling and a microbial sensor, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is significantly overexpressed in CRC patients. We identified CEACAM1-SPTBN1 interactions at specific residues (E517 and Y520) within the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 cytoplasmic domain, with both molecules playing pivotal roles in CRC progression. Our study identifies mechanistic insights into how microbial metabolites target TGF-β a major signaling pathways to promote CRC.
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| Overall design |
Using RNA-seq to characterize transcriptional alterations in colon cancer cell line (HCT116) under different conditions: Control, TGF-β, NH4Cl, and NH4Cl plus TGF-β.
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| Contributor(s) |
Bhowmick K, Xiang X, Mishra L |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 11, 2024 |
| Last update date |
Nov 16, 2024 |
| Contact name |
Lopa Mishra |
| E-mail(s) |
[email protected]
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| Organization name |
The Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory
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| Street address |
350 Community Drive
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| City |
Manhasset |
| State/province |
NY |
| ZIP/Postal code |
11030 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| GSM8624895 |
TGF-β treatment, replicate 1, RNAseq |
| GSM8624896 |
TGF-β treatment, replicate 2, RNAseq |
| GSM8624897 |
TGF-β treatment, replicate 3, RNAseq |
| GSM8624898 |
NH4Cl treatment, replicate 1, RNAseq |
| GSM8624899 |
NH4Cl treatment, replicate 2, RNAseq |
| GSM8624900 |
NH4Cl treatment, replicate 3, RNAseq |
| GSM8624901 |
NH4Cl plus TGF-β treatment, replicate 1, RNAseq |
| GSM8624902 |
NH4Cl plus TGF-β treatment, replicate 2, RNAseq |
| GSM8624903 |
NH4Cl plus TGF-β treatment, replicate 3, RNAseq |
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| Relations |
| BioProject |
PRJNA1184799 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE281613_fpkm_C_vs_T_vs_N_vs_NT.txt.gz |
1.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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