Muscle-invasive bladder cancer (MIBC) is a highly aggressive urinary tract malignancy with a marked propensity for distant metastasis; over 50% of patients develop metastasis within 2 years of radical cystectomy, and median survival of metastatic cases falls below 16 months. Cisplatin-based chemotherapy offers limited survival benefit, and the mechanistic link between intramuscular invasion and distant metastasis has long remained elusive, creating an urgent unmet clinical need.
A research team led by Prof. Libing Song and Prof. Jun Li from Sun Yat-sen University Cancer Center conducted a comprehensive study to decode the metastatic mechanism of MIBC. Using 305 clinical bladder cancer specimens, patient-derived cancer cells, and orthotopic xenograft mouse models, the team first discovered that elevated intramuscular microvessel density (MVD) in MIBC is strongly associated with distant metastasis and poor survival. These intramuscular vessels co-express endothelial (CD31) and smooth muscle (α-SMA) markers, originating from SMCs transdifferentiated into endothelial-like cells (ELCs).
Further mechanistic studies revealed that MIBC cells secrete high levels of succinate, which drives SMC-to-ELC transdifferentiation through a two-step process:
1. Early-stage: Succinate activates the SUCNR1/MAPK pathway to initiate SMC dedifferentiation;
2. Late-stage: Succinate is taken up via the MCT1 transporter, inducing iNOS succinylation at K22 to stabilize iNOS and boost NO production, which promotes endothelial specification.
Succinate accumulation stems from reversed succinate dehydrogenase (SDH) activity fueled by SQOR-mediated ubiquinol (CoQH₂) overload. The team uncovered a non-canonical TGFβ3 signaling axis: TGFβ3 activates SMAD2 independently of SMAD3/4, forming a SMAD2/ETV4/CARM1 transcriptional complex that epigenetically upregulates SQOR via H3R17me2a modification, driving the metabolic-angiogenic cascade.
Through structure-based virtual screening targeting the SMAD2-ETV4 interface, the team identified L-chicoric acid as a potent inhibitor that directly binds SMAD2 and disrupts the ternary complex assembly. In vivo experiments confirmed that L-chicoric acid reduces SQOR expression and succinate levels, blocks SMC-to-ELC transdifferentiation, and drastically suppresses lung metastasis of MIBC without affecting tumor cell proliferation.
This study establishes the TGFβ3/SMAD2/ETV4/succinate axis as a key driver of MIBC metastasis and validates L-chicoric acid as a potential anti-metastatic candidate, providing a novel translational strategy for MIBC treatment.
This work entitled “TGFβ3-SMAD2/ETV4/CARM1 axis drives metastatic progression in Muscle-invasive Bladder Cancer via succinate metabolic rewiring” was published online 13 February, 2026, in Targetome.
DOI：10.48130/targetome-0026-0007