CTC-derived pancreatic cancer models serve as research tools and are suitable for precision medicine approaches

Jiajia Tang; Quan Zheng; Qi Wang; Yaru Zhao; Preeta Ananthanarayanan; Chiara Reina; Berina Šabanović; Ke Jiang; Ming-Hsin Yang; Clara Csilla Meny; Huimin Wang; Mette Ø Agerbaek; Thomas Mandel Clausen; Tobias Gustavsson; Chenlei Wen; Felice Borghi; Alfredo Mellano; Elisabetta Fenocchio; Vanesa Gregorc; Anna Sapino; Thor G Theander; Da Fu; Alexandra Aicher; Ali Salanti; Baiyong Shen; Christopher Heeschen

doi:10.1016/j.xcrm.2024.101692

CTC-derived pancreatic cancer models serve as research tools and are suitable for precision medicine approaches

Cell Rep Med. 2024 Sep 17;5(9):101692. doi: 10.1016/j.xcrm.2024.101692. Epub 2024 Aug 19.

Authors

Jiajia Tang¹, Quan Zheng¹, Qi Wang¹, Yaru Zhao¹, Preeta Ananthanarayanan², Chiara Reina², Berina Šabanović², Ke Jiang¹, Ming-Hsin Yang³, Clara Csilla Meny⁴, Huimin Wang¹, Mette Ø Agerbaek⁵, Thomas Mandel Clausen⁶, Tobias Gustavsson⁷, Chenlei Wen⁸, Felice Borghi⁹, Alfredo Mellano⁹, Elisabetta Fenocchio¹⁰, Vanesa Gregorc¹⁰, Anna Sapino¹¹, Thor G Theander⁶, Da Fu⁸, Alexandra Aicher¹², Ali Salanti⁶, Baiyong Shen¹³, Christopher Heeschen¹⁴

Affiliations

¹ Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy.
³ Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
⁴ 2(nd) Institute for Pathology and Experimental Oncology Research, Semmelweis University, 1085 Budapest, Hungary.
⁵ Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark; VarCT Diagnostics, Ole Maaloes vej 3, 2200 Copenhagen, Denmark.
⁶ Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark.
⁷ Centre for Translational Medicine and Parasitology (CMP) at Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen N, Denmark; VAR2Pharmaceuticals, Ole Maaloes vej 3, 2200 Copenhagen, Denmark.
⁸ Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁹ Department of Surgical Oncology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy.
¹⁰ Department of Medical Oncology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy.
¹¹ Department of Pathology, Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy.
¹² Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404328, Taiwan; Immunology Research and Development Center, China Medical University, Taichung 404328, Taiwan.
¹³ Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
¹⁴ Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, 10060 Candiolo, Turin, Italy. Electronic address: [email protected].

Abstract

Pancreatic ductal adenocarcinoma (PDAC) poses significant clinical challenges, often presenting as unresectable with limited biopsy options. Here, we show that circulating tumor cells (CTCs) offer a promising alternative, serving as a "liquid biopsy" that enables the generation of in vitro 3D models and highly aggressive in vivo models for functional and molecular studies in advanced PDAC. Within the retrieved CTC pool (median 65 CTCs/5 mL), we identify a subset (median content 8.9%) of CXCR4⁺ CTCs displaying heightened stemness and metabolic traits, reminiscent of circulating cancer stem cells. Through comprehensive analysis, we elucidate the importance of CTC-derived models for identifying potential targets and guiding treatment strategies. Screening of stemness-targeting compounds identified stearoyl-coenzyme A desaturase (SCD1) as a promising target for advanced PDAC. These results underscore the pivotal role of CTC-derived models in uncovering therapeutic avenues and ultimately advancing personalized care in PDAC.

Keywords: CXCR4; circulating cancer stem cells; compound screening; liquid biopsy; metabolism; pancreatic cancer.

MeSH terms

Aged
Animals
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Female
Humans
Male
Mice
Middle Aged
Neoplastic Cells, Circulating* / metabolism
Neoplastic Cells, Circulating* / pathology
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / pathology
Precision Medicine* / methods
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism
Stearoyl-CoA Desaturase / genetics
Stearoyl-CoA Desaturase / metabolism

Substances

Stearoyl-CoA Desaturase
Receptors, CXCR4
Biomarkers, Tumor