Rethinking Bladder Cancer: Hidden Biology, Multi-Scale Networks, and Counterintuitive Therapeutic Strategies
核心洞察
Bladder cancer (搜索) remains one of the most frequently diagnosed urologic malignancies worldwide, imposing a heavy and persistent burden on patients and health systems despite decades of progress.
A new research framework organizes bladder cancer (搜索) research around five strategically unconventional questions, spanning protective phenotypes, mutational epidemiology, the dark proteome, neural circuits, and microbiome-driven therapy.
The framework proposes a deliberately counterintuitive strategy that harnesses microbiome-driven modulation of cellular stress to push oncogenic pathways beyond their optimal range and induce lethal stress responses.
Bladder cancer (搜索) remains one of the most frequently diagnosed urologic malignancies worldwide, imposing a heavy and persistent burden on patients and health systems despite decades of technical and scientific progress. To address this stagnation, a new research framework proposes reorganizing bladder cancer research around five large, strategically unconventional questions, with the goal of moving beyond incremental refinement of existing tools toward fundamentally new questions about risk, hidden biology, systemic physiology, and treatment resistance.
Five Unconventional Questions
The first question asks why many individuals exposed to major risk factors — tobacco use, occupational carcinogens, and chronic infection — never develop the disease, in search of protective genetic, immune, or microbiome-related mechanisms that could inform prevention.
The second extends the mutational-epidemiology approach pioneered by international efforts linking mutational signatures with environmental and geographic exposures, using these patterns to explain geographic variation in incidence and potentially reveal previously unrecognized environmental carcinogens that continue to drive disease in specific regions.
The third focuses on the "poorly characterized proteome," a class of non-canonical proteins that are not readily predicted from known genes or mutations. Because urine provides direct, non-invasive access to the tumour surface, bladder cancer (搜索) represents a particularly powerful model for detecting these hidden protein products and evaluating their potential as neoantigens or biomarkers.
The fourth challenge examines the bladder as an innervated organ, exploring how neural circuits influence tumour growth, immune responses, and systemic symptoms such as pain and fatigue, as well as how tumours may in turn disrupt these circuits.
The fifth examines a deliberately counterintuitive therapeutic strategy framed within a multi-scale causality model of cancer, integrating the microbiome as a key modulator of tumour signalling and treatment response. Rather than solely inhibiting oncogenic pathways, it explores whether microbiome-driven modulation of cellular stress can be harnessed to drive signalling pathways and network players beyond their optimal activity range, thereby inducing lethal stress responses.
A Route to Overcome Therapeutic Resistance
This framework offers a potential route to overcome resistance to current targeted therapies by linking oncogenic hyperactivation to host–microbiome–tumour interactions across biological scales. The initiative aims to stimulate research that moves beyond incremental refinement of existing tools toward fundamentally new questions about risk, hidden biology, systemic physiology, and treatment resistance, with the goal of improving outcomes for patients with bladder cancer (搜索).
Scope of the Research Topic
To advance collective understanding of bladder cancer (搜索), the Research Topic welcomes only Original Research, Review, Mini Review, and Perspective articles addressing, but not limited to, the following topics: protective phenotypes and resistance to risk factors involving genetic, immune, and microbiota mechanisms in disease absence; mutational epidemiology and signatures shaping incidence and subtype variation; the dark proteome in urothelial carcinoma (搜索) comprising non-canonical proteins as biomarkers and neoantigens; neural circuits and the bladder–brain axis involving tumour innervation and neuro–tumour interactions; microbiome–tumour interactions regulating inflammation, metabolism, and therapy response; microbiome and therapeutic resistance driving resistance and sensitivity to therapies; multi-scale causality in bladder cancer linking molecular to ecosystem-level tumour drivers; and rewiring oncogenic signalling for therapy to exploit pathway hyperactivation and overcome resistance.
Case Reports are not accepted as part of the collection, and manuscripts consisting solely of bioinformatics or computational analysis of public databases, not supported by validation in independent cohorts or biological/clinical studies, are out of scope and will not be considered for this collection.