Tumor “waste” metabolite succinate rewires bladder muscle to build metastatic blood-vessel niches

Their mechanistic work identifies a coupled signaling–metabolic loop in which tumor-derived TGFβ3 triggers mitochondrial rewiring and succinate accumulation, converting this normally intracellular metabolite into a paracrine cue that prompts bladder smooth muscle cells to adopt endothelial-like features and build vascular niches that support metastatic spread.

Clinicians have long observed that once bladder tumors invade the detrusor muscle, the risk of lymph-node and distant metastasis rises sharply and outcomes worsen. Yet the biological “bridge” between muscle invasion and systemic dissemination has remained elusive. The detrusor is dominated by smooth muscle cells (SMCs), which can be surprisingly plastic under stress and disease. This plasticity raises a provocative possibility: invading tumors might not just pass through muscle, but instead instruct muscle-resident cells to remodel the local microenvironment—especially blood vessels—creating routes and supportive niches for metastatic seeding.

A study (DOI:10.48130/targetome-0026-0007) published in Targetome on 13 February 2026 by Miaoling Tang’s team, Sun Yat-Sen University, reveals how a tumor-driven TGFβ3–succinate metabolic signaling loop reprograms bladder smooth muscle into metastasis-supporting vascular niches, identifying actionable targets to block muscle-invasive bladder cancer spread.

Using an integrated pipeline of clinical pathology, patient-derived models, cell reprogramming assays, metabolomics, and targeted pathway inhibition, researchers first quantified intramuscular microvessel density (MVD) by immunohistochemistry in 305 archived bladder cancer specimens (NMIBC n=127; MIBC n=178), then tested causality in an orthotopic xenograft model built from 15 patient-derived bladder cancer lines (7 muscle-invasive, 8 non–muscle-invasive). They next established a co-culture/conditioned-medium system with human bladder smooth muscle cells (PBSMCs), fractionated tumor conditioned medium by size (<3 kDa vs >3 kDa), identified active metabolites by LC/MS, and validated the key candidate using exogenous supplementation and neutralizing antibodies; finally, they profiled temporal marker changes and used RNA-seq/GO and pharmacologic blockade to define the initiating signaling route. These approaches showed that MIBC tissues had significantly higher MVD within the muscularis than NMIBC, and high MVD correlated with shorter distant-metastasis–free and overall survival; notably, CD31⁺ microvessels in MIBC muscularis frequently co-expressed the smooth muscle marker α-SMA, suggesting a smooth muscle origin. In mice, muscle-invasive patient-derived tumors infiltrated the muscularis, displayed increased intramuscular CD31⁺ vessels, and produced lung metastases in 5/7 cases, whereas non–muscle-invasive tumors remained superficial with sparse vessels and no lung metastasis (0/8); multiplex IHC confirmed increased CD31⁺/α-SMA⁺ intramural vessels in the invasive group. In vitro, MI-PDBC co-culture or conditioned medium drove PBSMCs to lose α-SMA and gain endothelial markers (CD31, CD144, vWF), with enhanced tube formation and angiogenesis. Fractionation localized the inductive activity to the <3 kDa small-molecule fraction, and LC/MS pinpointed succinate as the markedly elevated metabolite. Exogenous succinate recapitulated the endothelial-like conversion and pro-angiogenic phenotypes, while a succinate-neutralizing antibody abolished them in vitro and reduced succinate-driven increases in intramuscular vessel density in vivo. Mechanistically, time-course profiling showed early loss of smooth muscle programs preceding delayed endothelial gene induction, and RNA-seq/GO plus inhibitor studies indicated that the initial dedifferentiation phase is triggered through SUCNR1-dependent MAPK/ERK signaling.

In conclusion, this work maps a druggable TGFβ3–SMAD2–SQOR–succinate axis that converts bladder smooth muscle into endothelial-like, metastasis-supporting vasculature. Multiple intervention points emerge—from blocking TGFβ3–SMAD2 signaling and SQOR-driven succinate production to neutralizing succinate or inhibiting SUCNR1 and MCT1/iNOS. Notably, L-chicoric acid disrupts the SMAD2–ETV4 interface, reduces succinate and hybrid vessels, and limits lung metastasis in mice.

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References

DOI

10.48130/targetome-0026-0007

Original Source URL

https://doi.org/10.48130/targetome-0026-0007

Funding information

This work was supported by the Shenzhen Medical Research Fund (B2302046, B2502006) and Natural Science Foundation of China (No. 82330082, 82573270, 82203746, 82460551); The Special Program for Basic Research (Natural Science Foundation) of Shenzhen (No. JCYJ20230807114100001 to Hequn Zou).

About Targetome

Targetome refers to the complete collection of molecular targets (e.g., proteins, RNA or DNA) that interact with and mediate the effect of a specific biomolecule, such as a drug, toxin, metabolites, transcription factor or microRNA, within a biological system. Targetome is an open access journal publishing rigorously peer-reviewed original research articles, reviews, break-through methods, and perspectives that advance our understanding, identification and validation of molecular targets for new drug development.