Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion
Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcr...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-04-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI162054 |
| _version_ | 1797634515582058496 |
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| author | Yea Ji Jeong Hildur Knutsdottir Fatemeh Shojaeian Michael G. Lerner Maria F. Wissler Elodie Henriet Tammy Ng Shalini Datta Bernat Navarro-Serer Peter Chianchiano Benedict Kinny-Köster Jacquelyn W. Zimmerman Genevieve Stein-O’Brien Matthias M. Gaida James R. Eshleman Ming-Tseh Lin Elana J. Fertig Andrew J. Ewald Joel S. Bader Laura D. Wood |
| author_facet | Yea Ji Jeong Hildur Knutsdottir Fatemeh Shojaeian Michael G. Lerner Maria F. Wissler Elodie Henriet Tammy Ng Shalini Datta Bernat Navarro-Serer Peter Chianchiano Benedict Kinny-Köster Jacquelyn W. Zimmerman Genevieve Stein-O’Brien Matthias M. Gaida James R. Eshleman Ming-Tseh Lin Elana J. Fertig Andrew J. Ewald Joel S. Bader Laura D. Wood |
| author_sort | Yea Ji Jeong |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-β1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs. |
| first_indexed | 2024-03-11T12:08:56Z |
| format | Article |
| id | doaj.art-877a49b959a144a8a641ca1dc42fec86 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:56Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-877a49b959a144a8a641ca1dc42fec862023-11-07T16:20:12ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-04-011338Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasionYea Ji JeongHildur KnutsdottirFatemeh ShojaeianMichael G. LernerMaria F. WisslerElodie HenrietTammy NgShalini DattaBernat Navarro-SererPeter ChianchianoBenedict Kinny-KösterJacquelyn W. ZimmermanGenevieve Stein-O’BrienMatthias M. GaidaJames R. EshlemanMing-Tseh LinElana J. FertigAndrew J. EwaldJoel S. BaderLaura D. WoodPancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-β1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs.https://doi.org/10.1172/JCI162054GastroenterologyOncology |
| spellingShingle | Yea Ji Jeong Hildur Knutsdottir Fatemeh Shojaeian Michael G. Lerner Maria F. Wissler Elodie Henriet Tammy Ng Shalini Datta Bernat Navarro-Serer Peter Chianchiano Benedict Kinny-Köster Jacquelyn W. Zimmerman Genevieve Stein-O’Brien Matthias M. Gaida James R. Eshleman Ming-Tseh Lin Elana J. Fertig Andrew J. Ewald Joel S. Bader Laura D. Wood Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion The Journal of Clinical Investigation Gastroenterology Oncology |
| title | Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion |
| title_full | Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion |
| title_fullStr | Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion |
| title_full_unstemmed | Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion |
| title_short | Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion |
| title_sort | morphology guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion |
| topic | Gastroenterology Oncology |
| url | https://doi.org/10.1172/JCI162054 |
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