Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer
Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular ima...
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| Veröffentlicht in: | Cell 2024-12, Vol.187 (25), p.7232-7247.e23 |
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| creator | You, Eunae Danaher, Patrick Lu, Chenyue Sun, Siyu Zou, Luli Phillips, Ildiko E. Rojas, Alexandra S. Ho, Natalie I. Song, Yuhui Raabe, Michael J. Xu, Katherine H. Richieri, Peter M. Li, Hao Aston, Natalie Porter, Rebecca L. Patel, Bidish K. Nieman, Linda T. Schurman, Nathan Hudson, Briana M. North, Khrystyna Church, Sarah E. Deshpande, Vikram Liss, Andrew S. Kim, Tae K. Cui, Yi Kim, Youngmi Greenbaum, Benjamin D. Aryee, Martin J. Ting, David T. |
| description | Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.
[Display omitted]
•Single-molecule imaging provides a spatial map of repeat and coding RNAs in human PDAC•Interferon response to repeat RNAs perturbs multiple cell types in PDAC tumor•Repeat RNA delivery to stromal cells via extracellular vesicles analogous to a virus•Divergent responses to repeat RNAs between CAFs and PDAC cells are driven by IRF3
Single-molecule spatial imaging in human pancreatic cancers identifies aberrant repeat RNA expression in cancer cells and the surrounding tumor microenvironment linked with alterations in cell fate induced by an interferon response to the viral-like behavior of repeat elements. |
| doi_str_mv | 10.1016/j.cell.2024.09.024 |
| format | Article |
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[Display omitted]
•Single-molecule imaging provides a spatial map of repeat and coding RNAs in human PDAC•Interferon response to repeat RNAs perturbs multiple cell types in PDAC tumor•Repeat RNA delivery to stromal cells via extracellular vesicles analogous to a virus•Divergent responses to repeat RNAs between CAFs and PDAC cells are driven by IRF3
Single-molecule spatial imaging in human pancreatic cancers identifies aberrant repeat RNA expression in cancer cells and the surrounding tumor microenvironment linked with alterations in cell fate induced by an interferon response to the viral-like behavior of repeat elements.</description><identifier>ISSN: 0092-8674</identifier><identifier>ISSN: 1097-4172</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2024.09.024</identifier><identifier>PMID: 39383862</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>cancer-associated fibroblast ; Cancer-Associated Fibroblasts - metabolism ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - metabolism ; Carcinoma, Pancreatic Ductal - pathology ; Cell Line, Tumor ; Cell Plasticity ; cellular plasticity ; extracellular vesicles ; Extracellular Vesicles - metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity, Innate ; Interferon Regulatory Factor-3 - metabolism ; Myofibroblasts - metabolism ; pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; repeat RNA ; RNA - metabolism ; Signal Transduction ; spatial transcriptomics ; Tumor Microenvironment</subject><ispartof>Cell, 2024-12, Vol.187 (25), p.7232-7247.e23</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c237t-f67a2d7e704a8ac20ab37bb585cdac654fa4555b4ae3c2d8ecfe4513762a97ed3</cites><orcidid>0000-0002-3261-2322 ; 0000-0001-9028-4024</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867424010729$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39383862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>You, Eunae</creatorcontrib><creatorcontrib>Danaher, Patrick</creatorcontrib><creatorcontrib>Lu, Chenyue</creatorcontrib><creatorcontrib>Sun, Siyu</creatorcontrib><creatorcontrib>Zou, Luli</creatorcontrib><creatorcontrib>Phillips, Ildiko E.</creatorcontrib><creatorcontrib>Rojas, Alexandra S.</creatorcontrib><creatorcontrib>Ho, Natalie I.</creatorcontrib><creatorcontrib>Song, Yuhui</creatorcontrib><creatorcontrib>Raabe, Michael J.</creatorcontrib><creatorcontrib>Xu, Katherine H.</creatorcontrib><creatorcontrib>Richieri, Peter M.</creatorcontrib><creatorcontrib>Li, Hao</creatorcontrib><creatorcontrib>Aston, Natalie</creatorcontrib><creatorcontrib>Porter, Rebecca L.</creatorcontrib><creatorcontrib>Patel, Bidish K.</creatorcontrib><creatorcontrib>Nieman, Linda T.</creatorcontrib><creatorcontrib>Schurman, Nathan</creatorcontrib><creatorcontrib>Hudson, Briana M.</creatorcontrib><creatorcontrib>North, Khrystyna</creatorcontrib><creatorcontrib>Church, Sarah E.</creatorcontrib><creatorcontrib>Deshpande, Vikram</creatorcontrib><creatorcontrib>Liss, Andrew S.</creatorcontrib><creatorcontrib>Kim, Tae K.</creatorcontrib><creatorcontrib>Cui, Yi</creatorcontrib><creatorcontrib>Kim, Youngmi</creatorcontrib><creatorcontrib>Greenbaum, Benjamin D.</creatorcontrib><creatorcontrib>Aryee, Martin J.</creatorcontrib><creatorcontrib>Ting, David T.</creatorcontrib><title>Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer</title><title>Cell</title><addtitle>Cell</addtitle><description>Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.
[Display omitted]
•Single-molecule imaging provides a spatial map of repeat and coding RNAs in human PDAC•Interferon response to repeat RNAs perturbs multiple cell types in PDAC tumor•Repeat RNA delivery to stromal cells via extracellular vesicles analogous to a virus•Divergent responses to repeat RNAs between CAFs and PDAC cells are driven by IRF3
Single-molecule spatial imaging in human pancreatic cancers identifies aberrant repeat RNA expression in cancer cells and the surrounding tumor microenvironment linked with alterations in cell fate induced by an interferon response to the viral-like behavior of repeat elements.</description><subject>cancer-associated fibroblast</subject><subject>Cancer-Associated Fibroblasts - metabolism</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Plasticity</subject><subject>cellular plasticity</subject><subject>extracellular vesicles</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>Interferon Regulatory Factor-3 - metabolism</subject><subject>Myofibroblasts - metabolism</subject><subject>pancreatic cancer</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>repeat RNA</subject><subject>RNA - metabolism</subject><subject>Signal Transduction</subject><subject>spatial transcriptomics</subject><subject>Tumor Microenvironment</subject><issn>0092-8674</issn><issn>1097-4172</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLxDAUhYMozjj6B1xIlm5a82xacDP4xkFBdB3S9BYzdNqatML8e1NmdOnqXC7nHO79EDqnJKWEZlfr1ELTpIwwkZIijXKA5pQUKhFUsUM0J6RgSZ4pMUMnIawJIbmU8hjNeMFznmdsjp5vXfBjP7iuxV2Np8KxMR73jQmDs27Y4nKLPfRgBvz2sgzYtfhz3JgW96a1Pq6dxTaO4E_RUW2aAGd7XaCP-7v3m8dk9frwdLNcJZZxNSR1pgyrFCgiTG4sI6bkqixlLm1lbCZFbUQ8sxQGuGVVDrYGISlXGTOFgoov0OWut_fd1whh0BsXpstNC90YNKdUkkKqrIhWtrNa34Xgoda9dxvjt5oSPUHUaz0l9QRRk0JHiaGLff9YbqD6i_xSi4brnQHil98OvA7WQURQOQ920FXn_uv_AUhog6g</recordid><startdate>20241212</startdate><enddate>20241212</enddate><creator>You, Eunae</creator><creator>Danaher, Patrick</creator><creator>Lu, Chenyue</creator><creator>Sun, Siyu</creator><creator>Zou, Luli</creator><creator>Phillips, Ildiko E.</creator><creator>Rojas, Alexandra S.</creator><creator>Ho, Natalie I.</creator><creator>Song, Yuhui</creator><creator>Raabe, Michael J.</creator><creator>Xu, Katherine H.</creator><creator>Richieri, Peter M.</creator><creator>Li, Hao</creator><creator>Aston, Natalie</creator><creator>Porter, Rebecca L.</creator><creator>Patel, Bidish K.</creator><creator>Nieman, Linda T.</creator><creator>Schurman, Nathan</creator><creator>Hudson, Briana M.</creator><creator>North, Khrystyna</creator><creator>Church, Sarah E.</creator><creator>Deshpande, Vikram</creator><creator>Liss, Andrew S.</creator><creator>Kim, Tae K.</creator><creator>Cui, Yi</creator><creator>Kim, Youngmi</creator><creator>Greenbaum, Benjamin D.</creator><creator>Aryee, Martin J.</creator><creator>Ting, David T.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3261-2322</orcidid><orcidid>https://orcid.org/0000-0001-9028-4024</orcidid></search><sort><creationdate>20241212</creationdate><title>Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer</title><author>You, Eunae ; 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To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.
[Display omitted]
•Single-molecule imaging provides a spatial map of repeat and coding RNAs in human PDAC•Interferon response to repeat RNAs perturbs multiple cell types in PDAC tumor•Repeat RNA delivery to stromal cells via extracellular vesicles analogous to a virus•Divergent responses to repeat RNAs between CAFs and PDAC cells are driven by IRF3
Single-molecule spatial imaging in human pancreatic cancers identifies aberrant repeat RNA expression in cancer cells and the surrounding tumor microenvironment linked with alterations in cell fate induced by an interferon response to the viral-like behavior of repeat elements.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39383862</pmid><doi>10.1016/j.cell.2024.09.024</doi><orcidid>https://orcid.org/0000-0002-3261-2322</orcidid><orcidid>https://orcid.org/0000-0001-9028-4024</orcidid></addata></record> |
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| subjects | cancer-associated fibroblast Cancer-Associated Fibroblasts - metabolism Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cell Line, Tumor Cell Plasticity cellular plasticity extracellular vesicles Extracellular Vesicles - metabolism Gene Expression Regulation, Neoplastic Humans Immunity, Innate Interferon Regulatory Factor-3 - metabolism Myofibroblasts - metabolism pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology repeat RNA RNA - metabolism Signal Transduction spatial transcriptomics Tumor Microenvironment |
| title | Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer |
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