First molecule identified that promotes gut healing while inhibiting tumor progression
In a recent publication in Nature, researchers from CMM show that the molecule called Liver X receptor (LXR) can both help the intestines to heal after damage and suppress tumour growth in colorectal cancer. The discovery could lead to new treatments for inflammatory bowel disease (IBD) and cancer.
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 CMM Group and at the Department of Medicine, Solna, Karolinska Institutet. “We’ve now identified a molecule that can help the intestines to heal after damage while suppressing tumour growth in colorectal cancer.”
New drug candidates
This molecule is a protein called the Liver X receptor (LXR) and it was found among the handful of molecules with drug-candidate potential for treatment of IBD, identified by the research team.The strength of LXR as a IBD drug candidate lies in its capacity to both promote regeneration and suppress tumour growth in colorectal cancer.
“The discovery of both these functions was astonishing,” says CMM Group Leader 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. They 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.
Third most common cancer
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.
This text is based on an article from Karolinska Institutet.
Publication: ”Liver X receptor unlinks intestinal regeneration and tumorigenesis”, Srustidhar Das, S. Martina. Parigi, Xinxin Luo, Jennifer Fransson, Bianca Carola Kern, Ali Okhovat, Oscar E. Diaz, Chiara Sorini, Paulo Czarnewski, Anna T. Webb, Rodrigo A. Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P. Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A. Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J. Villablanca, Nature, online November 20 2024, doi: 10.1038/s41586-024-08247-6.