2. Academic Validation
  3. Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression

Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression

  • Cancer Discov. 2024 Aug 13. doi: 10.1158/2159-8290.CD-24-0287.
Hiroki Kobayashi 1,  Tadashi Iida 2,  Yosuke Ochiai 1,  Ermanno Malagola 1,  Xiaofei Zhi 1,  Ruth A White 3,  Jin Qian 1,  Feijing Wu 1,  Quin T Waterbury 1,  Ruhong Tu 4,  Biyun Zheng 1,  Jonathan S LaBella 1,  Leah B Zamechek 5,  Atsushi Ogura 6,  Susan L Woods 7,  Daniel L Worthley 8,  Atsushi Enomoto 9,  Timothy C Wang 1
Affiliations

Affiliations

  • 1 Columbia University Medical Center, New York, NY, United States.
  • 2 Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 3 NYU Langone's Laura and Isaac Perlmutter Cancer Center, New York, NY, United States.
  • 4 Union Hospital, Fuzhou, Fujian, China.
  • 5 Columbia University, New York, New York, United States.
  • 6 Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • 7 University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • 8 Colonoscopy Clinic, Brisbane, QLD, Australia.
  • 9 Nagoya University, Nagoya, Japan.
PMID: 39137067 DOI: 10.1158/2159-8290.CD-24-0287
Abstract

Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each Other to regulate Cancer progression. We found that in colorectal Cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/Akt pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and Akt activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk Inhibitor may represent a potential therapeutic approach for CRC.

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