New Publications Understanding the molecular signature of rare brain tumors

Researchers in the lab of Dr. Annarita Patrizi, a junior research group leader at DKFZ, and her collaborators have uncovered a crucial molecular pathway underlying the onset of choroid plexus tumors (CPTs). Tumors of the choroid plexus (ChP) develop when the specialized epithelial cells, known to produce the cerebrospinal fluid that bathes the brain and spinal cord, proliferate uncontrollably. Choroid plexus tumors are very rare, but are among the most common neoplasms of the central nervous system in infants under one year of age. It is noteworthy that they can already be detected in the third trimester of pregnancy.

Choroid plexus tumors can be categorized into the rather benign choroid plexus papillomas and the malignant choroid plexus carcinomas. Papillomas are highly treatable, whereas the prognosis for carcinomas is unfavorable. Due to their rarity, these tumors have not been well studied and to this day no specific cancer-driving mutations have been identified. By implementing an interdisciplinary approach involving techniques ranging from bioinformatics to genomic methodologies, Patrizi’s group identified a particularly high number of chromosomal deviations in the so-called Wnt/β-catenin signaling pathway in human choroid plexus tumors. This important intracellular pathway is well-known to be involved in many embryonic developmental events. In adult cells, the signaling pathway is mostly inactive, but in tumor cells it can be reactivated.

After confirming the constitutive activation of the Wnt/β-catenin pathway in human cancer cells, the researchers demonstrated that cells derived from choroid plexus tumors depend on Wnt/β-catenin activity for their survival and growth. In addition, they could demonstrate that boosting Wnt/β-catenin activity is sufficient for choroid plexus cells to develop tumor-typical properties such as accelerated proliferation and invasive potential. The researchers also established choroid plexus-organoids derived from induced pluripotent stem cells and used CRISPR-Cas9 technology to manipulate these to create the first 3D model for choroid plexus tumors using human cells.

These exciting findings open heretofore unavailable new avenues for therapeutic development of choroid plexus tumors. Due to its important role in tissue development and homeostasis, the Wnt/β-catenin pathway may be an attractive but challenging target for precision oncology. Several clinical trials are currently underway to inhibit this pathway using various strategies, but so far, no clinical trials targeting this pathway have been undertaken in patients with choroid plexus tumors.

The research work was funded by the Chica and Heinz Schaller Foundation and supported by the Hector Stiftung, the German Research Foundation and the Cancer-TRAX program.

The findings were published in the journal Neuro-Oncology.