The stromal microenvironment endows pancreatic neuroendocrine tumors with spatially specific invasive and metastatic phenotypes

Zeng Ye; Qiang Li; Yuheng Hu; Haifeng Hu; Junfeng Xu; Muzi Guo; Wuhu Zhang; Xin Lou; Yan Wang; Heli Gao; Desheng Jing; Guixiong Fan; Yi Qin; Yue Zhang; Xuemin Chen; Jie Chen; Xiaowu Xu; Xianjun Yu; Mingyang Liu; Shunrong Ji

doi:10.1016/j.canlet.2024.216769

The stromal microenvironment endows pancreatic neuroendocrine tumors with spatially specific invasive and metastatic phenotypes

Cancer Lett. 2024 Apr 28:588:216769. doi: 10.1016/j.canlet.2024.216769. Epub 2024 Mar 2.

Authors

Zeng Ye¹, Qiang Li², Yuheng Hu¹, Haifeng Hu¹, Junfeng Xu¹, Muzi Guo³, Wuhu Zhang¹, Xin Lou¹, Yan Wang¹, Heli Gao¹, Desheng Jing¹, Guixiong Fan¹, Yi Qin¹, Yue Zhang⁴, Xuemin Chen⁴, Jie Chen⁵, Xiaowu Xu⁶, Xianjun Yu⁷, Mingyang Liu⁸, Shunrong Ji⁹

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
² Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr.15, 81377, Munich, Germany.
³ Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴ Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
⁵ Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁶ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: xuxiaowu@fudanpci.org.
⁷ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yuxianjun@fudanpci.org.
⁸ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: liumy@cicams.ac.cn.
⁹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: jishunrong@fudanpci.org.

PMID: 38438098
DOI: 10.1016/j.canlet.2024.216769

Abstract

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP⁺ and α-SMA^high, were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-β expression in nearby tumor cells. Then, TGF-β promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis.

Keywords: Cell interaction; Spatial heterogeneity; Tumor cell plasticity; Tumor stroma.

MeSH terms

Cancer-Associated Fibroblasts* / metabolism
Cell Line, Tumor
Humans
Liver Neoplasms* / pathology
Neuroendocrine Tumors* / pathology
Pancreatic Neoplasms* / pathology
Phenotype
Transforming Growth Factor beta / metabolism
Tumor Microenvironment

Substances

Transforming Growth Factor beta