In October 2020 we said goodbye to Alessandra Merenda, who finished her post-doc in our lab. Alessandra started her new adventure as a scientist at HUB organoids. She received three gifts from the lab: a giant chocolate organoid cake, a jar of fortune candies (instead of fortune cookies), and a big photo book with personal messages from the group members. We will miss you, Alessa! And we hope to organize a proper goodbye dinner or borrel when this is allowed again.
In september 2020, the KWF (Royal Dutch Cancer Foundation) allocated 660.000 euros in funding for our lab to investigate how hereditary mutations in the LKB1 gene promote alterations in epithelial organization to generate a state of cancer predisposition in patients suffering from Peutz-Jeghers syndrome. We will perform this research in collaboration with our neighbors of the group of professor Edwin Cuppen.
Our publication describing how RNF43 mutations mediate a tumor suppressor-to-oncogene switch in cancer is now online at the EMBO Journal. The full article can be found here.
A video summary of our findings can be found here.
Tumor suppressor genes play an essential role in preventing uncontrolled cell division and thereby prevent cancer initiation; similar to the brake in a car. According to the dogma, cancer mutations in such a tumor suppressor genes cause loss-of-function of the gene resulting in a dysfunctional brake leading to uncontrolled growth and cancer formation. However, mutations in genes often do not result in a complete loss of the encoded protein, but rather create a shorter truncated version of the protein. The role of which is often unclear.
We previously discovered that the tumor-suppressor RNF43 controls the growth of intestinal stem cells by performing a negative feedback role in the Wnt-signaling pathway. Mutations in RNF43 are found in a variety of cancer types, including colorectal, gastric, endometrial, and pancreatic cancer. Mutations that result in loss of RNF43 function, make cancer cells hypersensitive for inhibitors of the growth signal Wnt.
However, we discovered a completely new class of RNF43 mutations that result in a shorter truncated protein. Instead of loss-of-brake function, these mutations endow RNF43 with a novel oncogenic role. Oncogenic RNF43 mutations can activate the Wnt signaling pathway in a ligand-independent manner, similar to pressing the accelerator pedal in a car. We introduced these oncogenic RNF43 mutations in human colon organoids and found that these colon organoids became insensitive to Wnt inhibitors.
Our study, therefore, stresses the importance of understanding the oncogenic mechanisms of mutations that are found in cancer patients. This is important for improved patient stratification for applications of precision medicine
In collaboration with the labs of Raj Rohatgi and Andres Lebensohn, we investigated the mechanism of LGR independent Wnt signaling potentiation by R-spondin. The results of this study have now been published in Elife: “R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling.” Check out the publication here.
In August 2019, our group published a new paper in Open Biology on single molecule FISH in organoids. Read this new publication here.
In January 2019, our group published on VHHs targeting LRP5/6 in Nature Communications. Check this new publication here.
In April 2018, our new paper on the role of TMEM59 in the Wnt signaling pathway was published. Check this new publication here.