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| Status |
Public on Jul 13, 2022 |
| Title |
Collagenolysis dependent DDR1 signaling dictates pancreatic cancer outcome |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer, frequently progressing and spreading by liver metastasis. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support or restrain PDAC progression and may impede blood supply and nutrient availability. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-kB-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are iCol I enriched and DDR1 and NRF2 low have improved median survival compared to those with high cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-kB or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. The diverse effects of the tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-kB-NRF2-mitochondrial biogenesis pathway, presenting new therapeutic opportunities.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for KPC960 (KPC) cells plated on WT ECM or MMP-resistant Col I (RR) ECM and incubated in low glucose (G) or low glutamine (Q) for 24 h.
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| Contributor(s) |
Su H, Yang F, Karin M |
| Citation(s) |
36198801 |
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| Submission date |
Jun 15, 2022 |
| Last update date |
Oct 12, 2022 |
| Contact name |
Hua Su |
| E-mail(s) |
husu@health.ucsd.edu
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| Organization name |
University of California, San Diego
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| Street address |
9500 Gilman Drive
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| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92093 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA849639 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE206218_KPC_ECM_lfdr.txt.crdownload.xlsx |
1.8 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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