An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
Background: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: An integrated model named “m6Ascore” is constructed based on RNA-seq...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-03-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421000645 |
| _version_ | 1818959485685727232 |
|---|---|
| author | Zhijun Zhou Junxia Zhang Chao Xu Jingxuan Yang Yuqing Zhang Mingyang Liu Xiuhui Shi Xiaoping Li Hanxiang Zhan Wei Chen Lacey R. McNally Kar-Ming Fung Wenyi Luo Courtney W. Houchen Yulong He Changhua Zhang Min Li |
| author_facet | Zhijun Zhou Junxia Zhang Chao Xu Jingxuan Yang Yuqing Zhang Mingyang Liu Xiuhui Shi Xiaoping Li Hanxiang Zhan Wei Chen Lacey R. McNally Kar-Ming Fung Wenyi Luo Courtney W. Houchen Yulong He Changhua Zhang Min Li |
| author_sort | Zhijun Zhou |
| collection | DOAJ |
| description | Background: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. Findings: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). Interpretation: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. Funding: This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center. |
| first_indexed | 2024-12-20T11:42:24Z |
| format | Article |
| id | doaj.art-45f0db65785742de978653edca4a8884 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-20T11:42:24Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-45f0db65785742de978653edca4a88842022-12-21T19:41:57ZengElsevierEBioMedicine2352-39642021-03-0165103271An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancerZhijun Zhou0Junxia Zhang1Chao Xu2Jingxuan Yang3Yuqing Zhang4Mingyang Liu5Xiuhui Shi6Xiaoping Li7Hanxiang Zhan8Wei Chen9Lacey R. McNally10Kar-Ming Fung11Wenyi Luo12Courtney W. Houchen13Yulong He14Changhua Zhang15Min Li16Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, Guangdong 518107, ChinaDepartment of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDepartment of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United StatesDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, Guangdong 518107, ChinaDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, Guangdong 518107, China; Corresponding authors.Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Corresponding authors.Background: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. Findings: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). Interpretation: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. Funding: This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center.http://www.sciencedirect.com/science/article/pii/S2352396421000645Pancreatic cancer, m6A regulatorsImmune evasionImmunotherapyRNA modification |
| spellingShingle | Zhijun Zhou Junxia Zhang Chao Xu Jingxuan Yang Yuqing Zhang Mingyang Liu Xiuhui Shi Xiaoping Li Hanxiang Zhan Wei Chen Lacey R. McNally Kar-Ming Fung Wenyi Luo Courtney W. Houchen Yulong He Changhua Zhang Min Li An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer EBioMedicine Pancreatic cancer, m6A regulators Immune evasion Immunotherapy RNA modification |
| title | An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer |
| title_full | An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer |
| title_fullStr | An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer |
| title_full_unstemmed | An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer |
| title_short | An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer |
| title_sort | integrated model of n6 methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer |
| topic | Pancreatic cancer, m6A regulators Immune evasion Immunotherapy RNA modification |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421000645 |
| work_keys_str_mv | AT zhijunzhou anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT junxiazhang anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT chaoxu anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT jingxuanyang anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT yuqingzhang anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT mingyangliu anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT xiuhuishi anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT xiaopingli anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT hanxiangzhan anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT weichen anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT laceyrmcnally anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT karmingfung anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT wenyiluo anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT courtneywhouchen anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT yulonghe anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT changhuazhang anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT minli anintegratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT zhijunzhou integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT junxiazhang integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT chaoxu integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT jingxuanyang integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT yuqingzhang integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT mingyangliu integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT xiuhuishi integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT xiaopingli integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT hanxiangzhan integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT weichen integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT laceyrmcnally integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT karmingfung integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT wenyiluo integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT courtneywhouchen integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT yulonghe integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT changhuazhang integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer AT minli integratedmodelofn6methyladenosineregulatorstopredicttumoraggressivenessandimmuneevasioninpancreaticcancer |