Identifying and eradicating tumour-initiating cells in high-risk cholangiocarcinoma patients

Background: Multiple cancers arise on the background of chronic disease; however, it remains unclear how tissue damage, inflammation and repair contribute to tumour formation.

Patients with primary sclerosing cholangitis (PSC), a chronic disease of the liver bile ducts (epithelial tubes made of cholangiocytes) are 400-times more likely to be diagnosed with a lethal liver cancer, cholangiocarcinoma (CCA) than the rest of the UK population. Cholangiocarcinoma is an aggressive and largely untreatable cancer that those living with PSC fear developing.

Subsequently, PSC patients defined that understanding why they are at a higher risk of developing CCA is important along with identifying routes to prevent CCA occurring. Our work shows that malignantly transformed cells behave differently in the presence of damage and tissue repair.

Mutant cholangiocytes acquire a particular injury-induced cell-state typified by the production of pro-inflammatory cytokines and we hypothesise that these specific cell states represent the earliest moments of tumour initiation in patients with PSC.

Furthermore, we propose that targeting and limiting the ability of these mutant cholangiocytes to establish an early, pre-neoplastic cancer microenvironment (by priming local immune cells) will ultimately reduce the likelihood that patients with PSC will develop CCA.

Aims: In this pilot project, we leverage our data generated from mouse models to ask: Aim-1: Do patients with PSC accumulate pre-neoplastic cells within their livers? Aim-2: Does selective targeting of pre-neoplastic cells limit tumour formation in PSC-to-CCA?

Methods: Using tissues from patients with PSC and those with PSC who then went on to develop CCA we will define whether the pre- and early-neoplastic cell states identified in our experimental model of PSC-driven CCA also occur in human disease.

We will then, using spatial transcriptional profiling, address how these pre-neoplastic cells condition their local immune microenvironment to support tumour initiation.

Finally, we will therapeutically inhibit the ability of these early neoplasms to pattern local immune cells and ask whether this limits their ability to contribute to cancer.

How the results of this research will be used: Patients with PSC are closely monitored for disease progression and cancer.

Because of this, there is a clearly defined and high-risk group of people who would benefit from prophylactic treatment which prevents them from develop an untreatable cancer.

More globally, we anticipate that our work will define some of the early molecular dependencies that all pre-neoplastic cells go through and address whether inhibiting those processes prevents tumour formation.