Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

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.

Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma

“…RNA velocity analysis was performed by scVelo to infer the future states of individual cells using the spliced and unspliced information as described in previous studies 18 , 56 . The aligned bam file generated by Cell Ranger was recounted with the Velocyto counting pipeline velocyto.py in python.…”

Macrophage diversity in human cancers: New insight provided by single-cell resolution and spatial context

“…Other interesting recent findings show new subsets of TAMs expressing markers uncommon for these cells. Thus, previously unknown TUBB3+ TAM subset showed a neuron-like transcriptome signature in lung cancer that was similar to the TUBB3+ neuronal cells associated with human neural diseases, but unlike the one revealed in TAMs by scRNA-seq [ 111 ]. TUBB3+ CD68+ TAM subset strongly expressed neuronal genes including BMP7, SHANK, CHL1 , and PAX6 in human non–small cell lung cancer (NSCLC) biopsy samples.…”

Tumour-associated macrophages: versatile players in the tumour microenvironment

“…Given the impact of cancer pain on quality of life, especially in patients with advanced stages of the disease (Wang et al, 2021c), understanding MNT is vital for pain management strategies. Notably, these transitions were found to be mediated by a Smad3-centric gene network in TAMs, highlighting the potential of macrophage-targeted Smad3 interventions as a promising therapeutic approach in cancer immunotherapy (Tang et al, 2017;Feng et al, 2018;Tang et al, 2021b;Tang et al, 2022b). These new findings lead to the development of effective therapeutic approaches to enhance the efficiency of conventional anticancer treatments as well as the latest immunotherapies which are not primary or secondary resistant in patients with solid cancers (Kim et al, 2019b;Kim et al, 2020;Tang et al, 2020;Chung et al, 2021; Xue et al, 2021).…”