1. Development of personalized immunotherapies for CRC patients

 

Cancer immunotherapy currently constitutes one of the most promising treatment options for cancer patients. We are working on the development of personalized neo-antigen-targeted immunotherapies, by applying next-generation sequencing technologies for the screening of cancer genomes in advanced colorectal cancer patients. This work is supported by the Fight Colorectal Cancer-Michael’s Mission-AACR Fellowship and the Bas Mulder Award 2015 (Alpe d'HuZes/KWF).

 

2. Discovery of novel immune cell subsets with anti-cancer activity

 

The diversity of immune cell entitites might be greater than expected. In a publication in 2012 [1] we described an immune cell subset that was specifically encountered in colorectal cancers that had not metastasized. By applying state-of-the-art technologies like mass cytometry and transcriptome sequencing we are working towards the characterization of this immune cell population. The ultimate objective of this endeavour is to develop a innovative immune cell therapy for metastatic cancer patients. This work is funded by the Veni ZonMw program.

 

3. Genetics of microsatellite-unstable colorectal cancer

Mutations in the TGFBR2 gene, encoding for a type 2 transmembrane kinase receptor required for transducing TGF-β signaling, are found in the majority of mismatch repair deficient colorectal cancers. We have recently discovered that TGFβ signaling remains active in some MSI-H colorectal cancer cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. In an accompanying editorial, this work was proposed to constitute a new paradigm in cancer genetics. [2, 3]

 

4. Genetics of familial colorectal cancer 

 

More than one-fourth of colorectal cancers display familial aggregation, while known cancer syndromes only contribute for approximately 6% of all colorectal cancers, which supports a strong role for elusive genetic factors in the etiology of this disease. We are applying next-generation sequencing technologies  for discovering novel genetic predisposition factors to colorectal cancer focusing on families with elevated burdens of colorectal cancer and individuals with young-onset colorectal cancer (< 50 years-old).

 

1. de Miranda NF, Goudkade D, Jordanova ES, Tops CM, Hes FJ, Vasen HF, van Wezel T, Morreau H. Infiltration of Lynch colorectal cancers by activated immune cells associates with early staging of the primary tumor and absence of lymph node metastases. Clin Cancer Res. 2012 ;18(5):1237-45.

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2. de Miranda NF, van Dinther M, van den Akker BE, van Wezel T, ten Dijke P, Morreau H. Transforming Growth Factor β Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2. Gastroenterology. 2015;148(7):1427-37.

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3. Grady, WM. Polymerase Slippage Restoration of Frameshifted TGFBR2 in Colorectal Cancer: A Novel Paradigm. Gastroenterology. 2015 Jun;148(7):1276-9.