Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies

Yu Zhang; Chengzhong Lin; Zheqi Liu; Yiting Sun; Mingtao Chen; Yibo Guo; Wei Liu; Chenping Zhang; Wantao Chen; Jian Sun; Ronghui Xia; Yuhua Hu; Xi Yang; Jiang Li; Zhiyuan Zhang; Wei Cao; Shuyang Sun; Xu Wang; Tong Ji

doi:10.1016/j.cmet.2022.10.012

Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies

Cell Metab. 2022 Dec 6;34(12):1999-2017.e10. doi: 10.1016/j.cmet.2022.10.012. Epub 2022 Nov 16.

Authors

Yu Zhang¹, Chengzhong Lin², Zheqi Liu¹, Yiting Sun³, Mingtao Chen¹, Yibo Guo¹, Wei Liu¹, Chenping Zhang¹, Wantao Chen¹, Jian Sun¹, Ronghui Xia⁴, Yuhua Hu⁴, Xi Yang¹, Jiang Li⁴, Zhiyuan Zhang¹, Wei Cao¹, Shuyang Sun⁵, Xu Wang⁶, Tong Ji⁷

Affiliations

¹ Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China.
² College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China; The 2nd Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
³ College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China; Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
⁴ College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China; Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
⁵ Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China. Electronic address: sunshuyang@sjtu.edu.cn.
⁶ Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China. Electronic address: wangx312016@sh9hospital.org.cn.
⁷ Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China. Electronic address: jitong70@hotmail.com.

PMID: 36395769
DOI: 10.1016/j.cmet.2022.10.012

Abstract

Although nutrient-starvation therapies can elicit strong anti-tumor effects in multiple carcinomas, it has been convincingly demonstrated that cancer cells exploit the tumor microenvironment to thrive in nutrient-poor environments. Here, we reveal that cancer cells can co-opt nociceptive nerves to thrive in nutrient-poor environments. Initially examining the low-glucose environment of oral mucosa carcinomas, we discovered that cancer cells employ ROS-triggered activation of c-Jun to secrete nerve growth factor (NGF), which conditions nociceptive nerves for calcitonin gene-related peptide (CGRP) production. The neurogenic CGRP subsequently induces cytoprotective autophagy in cancer cells through Rap1-mediated disruption of the mTOR-Raptor interaction. Both anti-glycolysis and anti-angiogenesis-based nutrient-starvation therapies aggravate the vicious cycle of cancer cells and nociceptive nerves and therapeutically benefit from blocking neurogenic CGRP with an FDA-approved antimigraine drug. Our study sheds light on the role of the nociceptive nerve as a microenvironmental accomplice of cancer progression in nutrient-poor environments and upon nutrient-starvation therapies.

Keywords: CGRP; angiogenesis; autophagy; cancer neuroscience; glycolysis; melanoma; nociceptive nerve; nutrient-starvation therapy; oral mucosa carcinomas; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma*
Humans
Tumor Microenvironment