Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain
Philip Chiu‐Tsun Tang, Jeff Yat‐Fai Chung, Jinyue Liao, Max Kam‐Kwan Chan, Alex Siu Wing Chan, Guangyao Cheng, Chunjie Li, Xiao‐Ru Huang, Calvin S.H. Ng, Eric W.‐F. Lam, Dongmei Zhang, Yi‐Ping Ho, Ka‐Fai To, Kam Tong Leung, Xiaohua Jiang, Ho Ko, TL Lee, Hui Y. Lan, Patrick Ming‐Kuen Tang
Abstract
Tumor innervation is a common phenomenon with unknown mechanism. Here, we discovered a direct mechanism of tumor-associated macrophage (TAM) for promoting de novo neurogenesis via a subset showing neuronal phenotypes and pain receptor expression associated with cancer-driven nocifensive behaviors. This subset is rich in lung adenocarcinoma associated with poorer prognosis. By elucidating the transcriptome dynamics of TAM with single-cell resolution, we discovered a phenomenon "macrophage to neuron-like cell transition" (MNT) for directly promoting tumoral neurogenesis, evidenced by macrophage depletion and fate-mapping study in lung carcinoma models. Encouragingly, we detected neuronal phenotypes and activities of the bone marrow-derived MNT cells (MNTs) in vitro. Adoptive transfer of MNTs into NOD/SCID mice markedly enhanced their cancer-associated nocifensive behaviors. We identified macrophage-specific Smad3 as a pivotal regulator for promoting MNT at the genomic level; its disruption effectively blocked the tumor innervation and cancer-dependent nocifensive behaviors in vivo. Thus, MNT may represent a precision therapeutic target for cancer pain.