Many patients with inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis do not respond to available treatments, highlighting the need to identify novel therapeutic strategies. In a new study published in Nature, researchers propose that promoting mucosal healing through tissue regeneration could be a valid alternative to immunosuppressive drugs.
"However, it’s virtually impossible to promote tissue regeneration without the risk of inducing tumour growth, as cancer cells can hijack the body's natural healing processes and start to grow uncontrollably," says lead author Srustidhar Das, research specialist in Eduardo Villablanca’s research group at Karolinska Institutet's Department of Medicine in Solna. "We've now identified a molecule that can help the intestines to heal after damage while suppressing tumour growth in colorectal cancer."
In their search for new ways to treat IBD, the researchers have identified a handful of molecules with drug-candidate potential. They found that activation of a protein called the Liver X receptor (LXR) can promote regeneration and suppress tumour growth in colorectal cancer.
"The discovery of both these functions was astonishing," says last author Eduardo J. Villablanca, Docent at Karolinska Institutet. "We now need to study how LXR controls tumour formation more closely."
The researchers used a collection of advanced technologies to conduct their study, which included mapping the transcriptome of intestinal cells. The researchers also cultivated what are known as 3D organoids: small, three-dimensional cell structures that mimic the function and structure of the body’s own organs, albeit in miniature format. They then used spatial transcriptomics to map the gene expression in the different tissues, a technique that has been developed at SciLifeLab by scientists from the Royal Institute of Technology (KTH) and Karolinska Institutet in Sweden.
Every year, over 7,000 people in Sweden develop bowel or rectal cancer, making it the third most common form of cancer in Sweden. Patients are often treated with chemotherapy and radiotherapy, but this can cause irritation and swelling of the bowel mucosa with subsequent chronic intestinal inflammation.
"Thus, this new therapeutic molecule has the potential to treat not only IBD patients but also cancer patients to prevent chronic bowel disorders after radiotherapy and/or chemotherapy," says Eduardo J. Villablanca.
The study was conducted with grants from several bodies, including the Swedish Research Council, Formas (The Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning), the Silicon Valley Community Foundation, Novo Nordisk, the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation and the Åke Wiberg Foundation.
Two of the authors have reported potential conflicts of interest: Eduardo J. Villablanca has received research funding from the pharmaceutical company F. Hoffmann-La Roche and Srustidhar Das works as a consultant for Cellphi Biotechnology AB.
Das S, Parigi SM, Luo X, Fransson J, Kern BC, Okhovat A, Diaz OE, Sorini C, Czarnewski P, Webb AT, Morales RA, Lebon S, Monasterio G, Castillo F, Tripathi KP, He N, Pelczar P, Schaltenberg N, De la Fuente M, López-Köstner F, Nylén S, Larsen HL, Kuiper R, Antonson P, Hermoso MA, Huber S, Biton M, Scharaw S, Gustafsson JÅ, Katajisto P, Villablanca EJ.
Liver X receptor unlinks intestinal regeneration and tumorigenesis.
Nature. 2024 Nov 20. doi: 10.1038/s41586-024-08247-6