Decoding Neural Circuits in Cholangiocarcinoma

Ziel

Cholangiocarcinoma (CCA) is a highly aggressive and therapy refractory liver cancer with alarming mortality, representing ~2% of all cancer-related deaths globally. Incidence and mortality rates have been increasing in the past few decades, and 5-year overall survival rates are still only 7-20%, highlighting the urgent need for new therapies. A major therapeutic barrier in CCA is the complex tumour microenvironment (TME), which shields tumour cells from effective immune responses. Recent studies have highlighted the role of nerve fibres in the TME and linked perineural invasion to cancer progression. However, the role of the nervous system in shaping the TME and how CCA may hijack neural signals for aggressive growth remains elusive.
My central hypothesis is that a multi-omic, spatial map of the neuro-hepatic axis, coupled with causal circuit modulation, will expose druggable pathways and yield a clinically usable neural signature. Preliminary data from my group show that sympathetic fibre density predicts worse survival in CCA, sympathetic innervation is increased in two CCA mouse models, and chemical sympathectomy reduces tumour burden with a shift toward cytotoxic immunity.

With LIVER-CIRCUITS I will
(I) create the first spatial multi-omic atlas of neural-tumour-immune niches in human CCA by pairing in situ RNA profiling with high-plex protein imaging and joint embedding with a single-cell atlas.
(II) Establish causality by tracing and modulating liver-innervating circuits using retrograde tracers and chemogenetics in preclinical models.
(III) Finally, deliver translation via a neural biomarker panel, trained and tested unchanged in two independent cohort, and validate targets in human-derived in-vitro systems to enable pharmacologic intervention.
My long-term vision for LIVER-CIRCUITS is to uncover fundamental mechanistic insights into nervous system-cancer interactions in CCA and translate these findings to new diagnostic tools and treatments.