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| Status |
Public on Feb 28, 2024 |
| Title |
SOX17 initiates an immune evasion program in early colorectal cancers [ATAC-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
In addition to accumulation of step-wise genetic mutations, epigenetic alterations play critical roles in the evolution of colon cancers. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish driver epigenetic alterations from passenger epigenetic alterations. To address this, we combined the colon cancer organoid orthotopic transplantation approach with comprehensive epigenomic and transcriptomic analyses. We found that an in vivo environment induces epigenetic alterations with fetal intestinal features that converge on SOX17, a transcription factor that is required for endoderm development. Surprisingly, SOX17 knockout leads to tumour rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumours into hot with robust infiltration of activated CD8+ T cells. Mechanistically, SOX17 suppresses Ifngr1-mediated MHC-I expression to evade CD8+ T cell-mediated tumour cell killing. At the tumour initiation, SOX17 expression is induced by APC loss, and SOX17 facilitates the production of LGR5- cells with low MHC-I expression to evade immune surveillance. Together, our result reveals that SOX17 is a master transcriptional factor that induces in vivo epigenetic reprograming of tumours, which provides fundamental understanding of how an immune evasion program is initiated at the early stages of colon cancer development.
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| Overall design |
We orthotopically transplanted naïve AKP organoids to immunocompetent mice by colonoscopy, generated organoids from the primary tumours, and passaged several times until only cancer cells are present in the culture.
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| Contributor(s) |
Goto N, Goto S, Agudo J, Yilmaz O |
| Citation(s) |
38418875 |
| |
| Submission date |
Jan 12, 2023 |
| Last update date |
Apr 12, 2024 |
| Contact name |
Norihiro Goto |
| E-mail(s) |
ngoto@mit.edu
|
| Organization name |
Massachusetts Institute of Technology
|
| Department |
Department of Biology
|
| Lab |
Yilmaz lab
|
| Street address |
500 Main Street, Building 76
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02139-4307 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (6)
|
| GSM6929255 |
Primary_tumor_AKP_replicate1 [ATAC_1010_Primary] |
| GSM6929256 |
Primary_tumor_AKP_replicate2 [ATAC_1026_Primary] |
| GSM6929257 |
Primary_tumor_AKP_replicate3 [ATAC_1027_Primary] |
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| This SubSeries is part of SuperSeries: |
| GSE222713 |
SOX17 initiates an immune evasion program in early colorectal cancers. |
|
| Relations |
| BioProject |
PRJNA923250 |
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