Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitat...
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creator | Sharma, Deepak Adnan, Darbaz Abdel-Reheem, Mostafa K Anafi, Ron C Leary, Daniel D Bishehsari, Faraz |
description | Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy. |
doi_str_mv | 10.1172/jci.insight.177697 |
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A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.177697</identifier><identifier>PMID: 38716727</identifier><language>eng</language><publisher>United States</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - pathology ; Cell Line, Tumor ; Chronotherapy - methods ; Circadian Clocks - drug effects ; Circadian Clocks - genetics ; Circadian Rhythm - genetics ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Organoids - drug effects ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Transcriptome</subject><ispartof>JCI insight, 2024-05, Vol.9 (9)</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c298t-98339f1a52cdaaded357a52c7ff3d9836a2d30e4f053de57e5944df9039ce9143</cites><orcidid>0000-0001-5644-2586</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38716727$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sharma, Deepak</creatorcontrib><creatorcontrib>Adnan, Darbaz</creatorcontrib><creatorcontrib>Abdel-Reheem, Mostafa K</creatorcontrib><creatorcontrib>Anafi, Ron C</creatorcontrib><creatorcontrib>Leary, Daniel D</creatorcontrib><creatorcontrib>Bishehsari, Faraz</creatorcontrib><title>Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets</title><title>JCI insight</title><addtitle>JCI Insight</addtitle><description>Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Line, Tumor</subject><subject>Chronotherapy - methods</subject><subject>Circadian Clocks - drug effects</subject><subject>Circadian Clocks - genetics</subject><subject>Circadian Rhythm - genetics</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Organoids - drug effects</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Transcriptome</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEtLAzEQx4MoVmq_gAfZo5eteWyazVGKLyh4UTwuYzLbpnSTNckKfnu3tIqnmWH-D_gRcsXonDHFb7fGzZ1Pbr3Jc6bUQqsTcsGF0qVQtD79t0_ILKUtpZSpilNZn5OJqBVbKK4uyPvSRQPWgS9yBJ9MdH0OHRahLXrwJiJkZwqw6IOBaJwPHRSDj_CFu1SYTQw-5A1G6HHYKzPENeZ0Sc5a2CWcHeeUvD3cvy6fytXL4_PyblUarutc6loI3TKQ3FgYS6yQan-othV2fC6AW0GxaqkUFqVCqavKtpoKbVCzSkzJzSG3j-FzwJSbziWDux14DENqBJVcaqEkG6X8IDUxpBSxbfroOojfDaPNnmkzMm2OTJsD09F0fcwfPjq0f5ZfguIH1H93nw</recordid><startdate>20240508</startdate><enddate>20240508</enddate><creator>Sharma, Deepak</creator><creator>Adnan, Darbaz</creator><creator>Abdel-Reheem, Mostafa K</creator><creator>Anafi, Ron C</creator><creator>Leary, Daniel D</creator><creator>Bishehsari, Faraz</creator><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/0000-0001-5644-2586</orcidid></search><sort><creationdate>20240508</creationdate><title>Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets</title><author>Sharma, Deepak ; 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A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.</abstract><cop>United States</cop><pmid>38716727</pmid><doi>10.1172/jci.insight.177697</doi><orcidid>https://orcid.org/0000-0001-5644-2586</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - pathology Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Cell Line, Tumor Chronotherapy - methods Circadian Clocks - drug effects Circadian Clocks - genetics Circadian Rhythm - genetics Gene Expression Regulation, Neoplastic - drug effects Humans Organoids - drug effects Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Transcriptome |
title | Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets |
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