Characterising and modulating cancer-associated ileopathy

Background

Whether gut dysbiosis is cause or consequence of tumor establishment and how it controls tumor progression remain open questions in immuno-oncology. Over the last 3 years, the Zitvogel lab has accumulated evidence showing that 50% of transplantable extra-intestinal experimental (mouse) malignancies as well as human cancers trigger a set of pathologies in the small intestine (the ileum), that were collectively named cancer-associated ileopathy. These defects include villus autophagy, apoptosis of crypt cells in the terminal ileum culminating in epithelial atrophy of the ileum, increased gut permeability, and protracted Gram+ related -dysbiosis that contribute to cancer growth and resistance to immunotherapy. This corollary syndrome of carcinogenesis coincides with neuroendocrine and Paneth cell activation and proliferation in mice and humans. Single cell transcriptomics and immunostainings revealed that stem cells and neuroendocrine cells upregulated neutrotransmitter signaling. Vancomycin (an antibiotic specific against Gram+ bacteria) and propranolol (an inhibitor of adrenaline signaling) could both transiently prevent cancer-associated ileopathy and antagonize tumor progression. The project thus aims at a) further deciphering the cellular (tumor, immune, neurological) or molecular/metabolic cues underlying cancer-associated ileopathy and b) identifying potential interceptive measures to inhibit the underlying vicious circle.

For more information on the study, visit NCT04079270 at clinicaltrials.gov

Goals

Use of high dimensional technologies such as ileal single cell transcriptomics and spatial transcriptomics to understand what pathological pathways are up- or downregulated when and where during cancer-associated ileopathy.
In vitro modelization using enteroids to identify the stimuli that contribute to the onset of ileopathy.
Description of the human syndrome: collaborative work with pathologists to identify neuroendocrine and neurological pathways in tissue sections and the specificity of the pathological disorder.
Determine what secretory components of tumours transduce a signal from the tumour to the ileal crypts.

The progress

Achieved Milestones

June

2021

Study Launch

Pre-clinical Testing

Data Analysis

Wrap up

Current status

Zitvogel Lab

Laurence Zitvogel

Principal Investigator