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| Status |
Public on Dec 01, 2023 |
| Title |
Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The sparse vascularity of Pancreatic Ductal Adenocarcinoma (PDAC) presents a mystery: what prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of non-canonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.
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| Overall design |
To investigate cell specific changes upon in vivo Smoothened inhibition, tumor bearing KPC mice were treated with either IPI-926 or vehicle for two days and collected tumor tissue for single cell RNA sequencing.
We then performed single cell regulatory network analysis, with a focus on the activity of Hedgehog, WNT, and VEGF signaling pathways.
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| Contributor(s) |
Hasselluhn MC, Decker-Farrell AR, Vlahos L, Thomas DH, Curiel-Garcia A, Maurer CH, Wasko UN, Tomassoni L, Sastra SA, Palermo CF, Dalton TC, Ma A, Li F, Tolosa EJ, Hibshoosh H, Fernandez-Zapico ME, Muir A, Califano A, Olive KP |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 06, 2023 |
| Last update date |
Dec 01, 2023 |
| Contact name |
Lukas Vlahos |
| E-mail(s) |
lv2395@cumc.columbia.edu
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| Organization name |
Columbia University
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| Department |
Systems Biology
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| Lab |
Andrea Califano
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| Street address |
1130 St Nicholas Ave
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| City |
New York City |
| State/province |
New York |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (6)
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| GSM7882922 |
Pancreatic Tumor Tissue, IPI-926, 2 days, KA003 |
| GSM7882923 |
Pancreatic Tumor Tissue, IPI-926, 2 days, KA005 |
| GSM7882924 |
Pancreatic Tumor Tissue, vehicle, 2 days, KA006 |
| GSM7882925 |
Pancreatic Tumor Tissue, vehicle, 2 days, KA007 |
| GSM7882926 |
Pancreatic Tumor Tissue, IPI-926, 2 days, KA008 |
| GSM7882927 |
Pancreatic Tumor Tissue, vehicle, 2 days, KA009 |
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| Relations |
| BioProject |
PRJNA1036165 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE247072_RAW.tar |
496.9 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
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