Integrative analysis reveals clinically relevant molecular fingerprints in pancreatic cancer

Libin Song; Simin Qi; Wei Hu; Zhixiao Fang; Dehua Yu; Teng Liu; Jingni Wu; Yangjun Wu; Aiwei Wu; Lanyun Feng; Jing Xie; Bo Zhang; Wenguang He; Zhouyu Ning; Luming Liu; Jiang-Jiang Qin; Shengli Li

doi:10.1016/j.omtn.2021.06.015

Integrative analysis reveals clinically relevant molecular fingerprints in pancreatic cancer

Mol Ther Nucleic Acids. 2021 Jul 2:26:11-21. doi: 10.1016/j.omtn.2021.06.015. eCollection 2021 Dec 3.

Authors

Libin Song^{1

2}, Simin Qi^{3

4}, Wei Hu⁵, Zhixiao Fang⁵, Dehua Yu^{3

4}, Teng Liu⁵, Jingni Wu⁵, Yangjun Wu⁶, Aiwei Wu⁷, Lanyun Feng^{1

2}, Jing Xie^{1

2}, Bo Zhang⁴, Wenguang He⁸, Zhouyu Ning^{1

2}, Luming Liu^{1

2}, Jiang-Jiang Qin^{3

4}, Shengli Li⁵

Affiliations

¹ Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
³ College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
⁴ The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
⁵ Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 201620, China.
⁶ Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁷ Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
⁸ Shanxi Provincial Cancer Hospital, Taiyuan 030013, China.

Abstract

Pancreatic cancer is a highly aggressive cancer with an exceedingly low rate of response to treatments, which calls for comprehensive molecular characterization of pancreatic cancer cell lines (PCCLs). We screened multi-layer molecular data of 36 PCCLs, including gene mutation, gene expression, microRNA (miRNA) expression, and protein profiles. Our comparative analysis of genomic mutations found that PCCLs recapitulated genomic alterations of the primary tumor and suggested potential therapeutic strategies for clinical interventions. The panel of 36 PCCLs was classified into 2 subgroups based on transcriptomic mRNA expression, wherein the C1 subgroup was characterized with differentiation, whereas C2 cell lines were featured with immunity, angiogenesis, epidermis, and proliferation. Transcriptomic classification was further recapitulated by miRNA and protein expression. Additionally, the differential proteins between C1 and C2 subgroups were prominently involved in epidermal growth factor receptor (EGFR) signaling, phosphatidylinositol 3-kinase (PI3K) signaling, and mitogen-activated protein kinase (MAPK) signaling pathways. Tumor samples from different subgroups exhibited distinct infiltration of CD4 naive cells and monocytes. Remarkably, patients in subgroups C1 showed longer survival, whereas those in C2 had worse clinical outcome. Further integrative analysis revealed that temozolomide and NVP-TAE684 showed higher sensitivity in the C1 subgroup, whereas the C2 cell lines were more sensitive to SR1001 and SRT-1720. Our results also showed that PCCLs with mutations in CDKN2A, TP53, and SMAD4 were more sensitive to certain anti-cancer drugs. Our integrative analysis identified molecular features of pancreatic cancer that were associated with clinical significance and drug sensitivity, providing potentially effective strategies for precision treatments of patients with pancreatic cancer.

Keywords: cancer cell lines; drug response; integrative analysis; multi-omics data; pancreatic cancer; pancreatic cancer subgroups.