Cancer-associated fibroblasts (CAF) 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, norepinephrine induces ADRB2 (β2-adrenergic receptor)–dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intratumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates colorectal cancer growth through ADRA2A/Gi-mediated activation of Yes-associated protein (YAP). NGF from CAFs directly enhances colorectal cancer cell growth via the phosphatidylinositol-3-kinase/AKT pathway. Treatment with a tropomyosin receptor kinase (TRK) inhibitor decreased YAP and AKT activation and colorectal cancer progression in mice. In human colorectal cancer, high NGF expression is associated with mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF–nerve cross-talk in promoting colorectal cancer progression. Blocking this feedforward loop with a TRK inhibitor may represent a potential therapeutic approach for colorectal cancer. Significance: Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.

Purpose: Pyroptosis plays an important role in tumor progression. However, there is no pyroptosis-associated long noncoding RNA (lncRNA) signature to predict the prognosis of patients with colorectal cancer (CRC). Materials and Methods: The RNA sequencing data (RNA-seq) and corresponding clinical information relating to CRC patients were obtained from the Cancer Genome Atlas (TCGA) database and the GSE39582 dataset. Univariate Cox regression analysis was used to identify pyroptosis-associated lncRNAs linked to CRC prognosis. Subsequently, multivariate Cox regression analysis was performed to construct a pyroptosis-associated lncRNAs signature within the TCGA cohort, which was then validated using the GSE39582 dataset. We used Kaplan–Meier (K-M) analysis, principal component analysis (PCA), and receiver operating characteristic curve (ROC) analysis to evaluate our novel lncRNA signature. Finally, gene set enrichment analysis (GSEA) was performed to explore the potential function of the lncRNA signature. Results: We constructed a pyroptosis-associated lncRNA signature comprising four lncRNAs (ELFN1-AS1, PCAT6, TNRC6C-AS1, and ZEB1-AS1). CRC patients were subdivided into high- and low-risk groups based on median risk scores. The results of the K-M, PCA, and ROC analyses showed that this signature could accurately predict the prognosis of CRC patients. Univariate and multivariate Cox regression analyses showed that the pyroptosis-associated signature was an independent prognostic factor. Functional analysis suggested that tumor-associated pathways were enriched for in the high-risk CRC patient group. Conclusion: Our study established an effective prognostic signature for CRC patients that may represent a potential therapeutic target.

The paradigm shift from molecular oncology to systems medicine reconceptualizes cancer from aberrant proliferative tissue to a pathological organ with systemic ramifications. This establishes a novel framework at the intersection of oncology and neurobiology, investigating neuro-tumor interactions through the innervation context of the anatomical site or organ harboring the tumor.

Background. Gastrointestinal stromal tumor (GIST) originates from a pacemaker cell, the Cajal cell. However, little is known about the cancer neuroscience in GIST. In this study, we aimed to elucidate the clinical and biological roles of adrenoceptor beta 2 (ADRB2) in GIST. Methods. Immunohistochemistry was used to evaluate the expression of ADRB2 in GIST tissues. The biological effects of ADRB2 on GIST cell proliferation, migration, invasion, and apoptosis were explored using Cell Counting Kit 8, plate colony formation assay, transwell invasion assay, and flow cytometry. We also explored the growth and metastasis of xenograft tumors in nude mice. Western blotting was used to quantify protein expression and phosphorylation. Results. ADRB2 is generally highly expressed in GIST. High ADRB2 expression was significantly associated with risk level, tumor size, mitotic count, and metastasis. Overexpression of ADRB2 promoted GIST cell proliferation, migration, invasion, and apoptosis, while silencing ADRB2 expression showed the opposite effects. Furthermore, we found that silencing endogenous ADRB2 inhibited GIST progression and metastasis in nude mice. ADRB2-induced ETV1 upregulation enhanced the activation of c-KIT. Conclusion. ADRB2 plays an important role in the proliferation and metastasis of GIST and is expected to be a potential target for the treatment of GIST.

Supplementary Figure S1 supports Figure 1 and shows stromal NGF expression and innervation in human colorectal cancer tissues. Supplementary Figure S2 supports Figure 1 and shows stromal NGF expression and innervation in mouse colorectal cancer tissues. Supplementary Figure S3 supports Figure 2 and shows that adrenergic stimulation induces fibroblast NGF upregulation via the β2-adrenergic receptor to promote innervation. Supplementary Figure S4 supports Figure 3 and shows that adrenergic stimulation increases mouse colon cancer organoid growth through ADRA2/Gi protein-mediated activation of YAP signaling. Supplementary Figure S5 supports Figure 3 and shows that adrenergic stimulation increases human colon cancer cell growth through ADRA2/Gi protein-mediated activation of YAP signaling. Supplementary Figure S6 supports Figure 3 and shows that chemical sympathectomy inhibits colon cancer growth and YAP activation. Supplementary Figure S7 supports Figure 4 and shows that stromal NGF increases innervation and colon cancer cell proliferation. Supplementary Figure S8 supports Figure 5 and shows that NGF increases colon cancer cell growth and stem-related gene expression. Supplementary Figure S9 supports Figure 6 and shows that Trk blockade decreases innervation, cancer cell proliferation, and Ngf expression. Supplementary Figure S10 supports Figure 7 and shows that high NGF expression is associated with poor patient outcomes, stroma-rich tumor subtypes, and enrichment for YAP and AKT pathways.