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Moonshot for Life

Quest to target one of the crucial signaling pathways in cancer goes on

The lab of Madelon Maurice, Ph.D. in the Netherlands is amongst the leading labs studying the role of Wnt signaling in cancer. A promising target for future cancer therapeutics?

Quest to target one of the crucial signaling pathways in cancer goes on

The lab of Madelon Maurice, Ph.D. in the Netherlands is amongst the leading labs studying the role of Wnt signaling in cancer. A promising target for future cancer therapeutics?

Madelon Maurice, professor of Molecular Cell Biology at the University Medical Center in Utrecht, The Netherlands, and a member of the national Oncode Institute for Cancer Research

Dysfunction of the Wingless-Int (Wnt) signaling pathway has been associated with various diseases, including cancer. Several molecular elements of the pathway hold promise for new innovative targets for cancer therapy.  The attention of scientists worldwide in terms of their therapeutic value for cancer is increasing. The Wnt signaling pathway has been intensively investigated by the lab of Madelon Maurice, professor of Molecular Cell Biology at the University Medical Center in Utrecht, The Netherlands, and a member of the national Oncode institute for cancer research. Her multidisciplinary research team is amongst the leading laboratories worldwide in the field of Wnt signaling.

Predicting relevant mutations

Nowadays, research databases are rapidly being filled with lists of genetic mistakes that occur in different cancer types. Cancer cells can accumulate from ten to a few thousands of such DNA mutations. “Only a few of those DNA mutations are important for cancer growth and progression. We aim to understand how these mutations exert impact on cancer cell function. This information allows us to better predict which mutations are relevant and develop more tailored treatment strategies”, says prof. Maurice. Her lab focuses on the mechanisms of signaling in stem cells and cancer. “Our primary research interests concern the molecular mechanisms by which Wnt signals guide stem cell maintenance and tumor cell growth.” The innovative nature of her work was awarded by an ERC Starting Grant (2009), a prestigious VICI grant (2014) and a recent ZonMW TOP grant (2019) from the Dutch Research Council.

Modulating Wnt signaling responses in stem cells and cancer

Led by prof. Maurice, a team of scientists at Oncode Institute, UMC Utrecht, University Utrecht, Isogenica (UK) and Attana (Sweden), identified single domain antibodies that block the receptors for Wnt. “Wnt signaling is a major cell-to-cell communication pathway that controls the maintenance and activity of stem cells. This pathway is frequently misused by cancer cells to allow them to divide and grow in an uncontrolled manner”, explains prof. Maurice. “Many tumors have errors in their Wnt signaling pathway due to mutations. Currently, clinical trials are ongoing that block the function of all 19 Wnt genes that are present in the human body. Due to the importance of Wnt signals in tissue maintenance, with this approach the risk of side effects for multiple tissues is very high. We hope it will be more efficient to instead only block those Wnts to which the cancer cell is addicted. We have focused on a subset of cancers where something is wrong with the receptors that capture the Wnt signals at the cell surface. Due to mutations these cancer cells accumulate too many receptors on their surface. As a result, the signaling mediated by these receptors is too strong and drives the growth of the tumor. We developed a strategy to block the binding of Wnts to these receptors with antibodies. When we add these antibodies to our preclinical tumor cultures, the cancer stem cell properties dissappear and the tumor cells stop growing.” The results of this study appeared recently in Nature Communications and show that antibody-mediated targeting of Wnt receptors provides a promising strategy for treatment of colorectal, pancreatic, ovarian and certain forms of liver cancer.

Adopting pioneering organoid technology

The lab is applying organoid technology, a breakthrough 3D culture technology to study mini organs in a dish. “We can now investigate the mechanisms of cell-to-cell communication in complex tissues because all cell types of the original tissue are present in these 3D cultures. We can compare diseased tissue with healthy tissue. We can study the response of certain medications. And, importantly, we can also model disease by inserting mutations that are important for cancer development using CRISPR-CAS9 technology. For instance, we can now correct mutations in patient-derived material and show which of the mutations that accumulated in a cancer cell are actually important.”

The Utrecht region in the Netherlands is at the forefront in applications of organoid technology that was pioneered by Hans Clevers, MD, PhD, group Leader at the Hubrecht Institute and Professor of Molecular Genetics at Utrecht University. The generation of patient-derived ‘living’ organoid biobanks now holds great promise to revolutionize healthcare and transform precision medicine. “For me, as a molecular cell biologist, it is very exciting to now be able to analyse and understand such complex tissues in detail. The number of applications of organoids in basic and translational research is rapidly expanding. I am convinced that these approaches will revolutionize the therapy of many severe diseases.”

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