Qiming Zhou

Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most fatal malignant tumors. Emerging studies have clarified the crucial roles of circular RNAs (circRNAs) in the tumorigenesis of cancers. CircVAPA was demonstrated to function in some human cancers. The present study aimed to investigate the role of circVAPA in NSCLC. METHODS: A quantitative real-time polymerase chain reaction was used to measure the expression of genes. Actinomycin D and RNase R were employed to examine the stability of circVAPA. Cell-counting kit-8, 5-ethynyl-2'-deoxyuridine, Transwell and sphere formation assays, and well as western blot analysis, were conducted to examine the changes of NSCLC cells in response to circVAPA knockdown. A luciferase reporter assay was conducted for the molecular mechanism. RESULTS: Our findings demonstrated high expression of circVAPA in tissues and cell lines of NSCLC. Knockdown of circVAPA had a suppressive effect on cell proliferation, migration, invasion and stemness, and also inhibited tumor growth in vivo. Mechanistically, circVAPA acted as a competing endogenous RNA to up-regulate WNT5A by sponging miR-876-5p. Moreover, circVAPA activated Wnt/β-catenin signaling by up-regulation of WNT5A. Rescue assays showed that silencing of miR-876-5p or overexpression of WNT5A reversed the circVAPA knockdown-mediated inhibition on cellular processes in NSCLC. CONCLUSIONS: CircVAPA promotes aggressive phenotypes of NSCLC cells by the miR-876-5p/WNT5A axis activating Wnt/β-catenin signaling.

Background and Purpose Chemotherapy‐induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. Experimental Approach Paclitaxel (PTX) was used to establish CINP. Quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot‐plate and von Frey tests. Whole‐cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. Key Results Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX‐treated mice. Additionally, OXTR activation up‐regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage‐gated sodium currents, particularly the voltage‐gated sodium channel 1.7 (Na V 1.7) current, that plays an indispensable role in PTX‐induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX‐treated mice. Conclusion and Implications The OXTR in small‐sized DRG neurons is up‐regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of Na V 1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP.

Chemotherapy resistance in colorectal cancer (CRC) remains a major obstacle in clinical oncology. Analysis of clinical specimens from chemotherapy-resistant patients revealed elevated CXCL7 expression in tumor-associated macrophages (TAMs). Through integrated in vitro and in vivo studies, we demonstrated that chemotherapy induces tumor cell-macrophage crosstalk, leading to CXCL7 upregulation in TAMs. Using a co-culture system, we observed that CXCL7+ macrophages confer chemoresistance to CRC cells. Mechanistic investigations revealed that CXCL7 activates the CXCR2 receptor on tumor cells, triggering interferon signaling and promoting serine metabolism through STAT1-dependent transcriptional upregulation of phosphoglycerate dehydrogenase (PHGDH), the key enzyme in serine biosynthesis. This metabolic reprogramming enhances the paracrine secretion of S-adenosyl methionine (SAM), which drives chemotherapy resistance. Furthermore, CXCL7-mediated the paracrine secretion of SAM in tumor cells, which in turn promotes M2 macrophage polarization and sustains CXCL7 expression in TAMs. Our findings reveal that a CXCL7-SAM feedback loop between tumor cells and macrophages establishes a chemoresistant niche. This interaction represents a promising therapeutic target for overcoming chemoresistance in CRC.

Abstract Anti‐PD‐1 immunotherapy and targeted therapy (TT) represent two major therapeutic modalities for BRAF V600 ‐mutant advanced melanoma, but the efficacy of combination therapy in Asian populations remains unknown. Asian melanoma patients differ significantly from Caucasians in tissue subtypes, pathogenesis and response to treatment. We retrospectively analyzed data of BRAF V600 ‐mutant advanced melanoma patients treated with first‐line vemurafenib (V) ± anti‐PD‐1 or dabrafenib+trametinib (D+T) ± anti‐PD‐1 between 2014 and 2023 from three centers in China. 178 patients were included, with V ( n = 45), D+T ( n = 51), V+anti‐PD‐1 ( n = 39) and D+T+anti‐PD‐1 ( n = 43). The median PFS (21.9 vs. 11.1 months, p < 0.001), OS (NR vs. 32.6 months, p = 0.027), and DoR (20.0 vs. 8.4 months, p = 0.002) were significantly prolonged with D+T+anti‐PD‐1 versus D+T. Addition of anti‐PD‐1 to V also significantly prolonged PFS, OS, and DoR ( p < 0.001). V+anti‐PD‐1 was superior to D+T in terms of PFS (15.0 vs. 11.1 months, p = 0.007) and DoR (18.0 vs. 8.4 months, p = 0.013), and was comparable to D+T+anti‐PD‐1. Addition of anti‐PD‐1 to BRAF inhibitor‐based TT was associated with lower incidence of brain metastases ( p = 0.032). Addition of anti‐PD‐1 to BRAF inhibitor‐based TT appears to be a safe and effective treatment option, conferring a survival benefit and delaying the onset brain metastases in patients with BRAF V600 ‐mutant advanced melanoma.