Research Projects

Pancreatic neuroendocrine tumours (PanNET) is a heterogenous group of tumours, which can be functional or non-functional depending on their ability to secrete active hormones. Genomic analyses of human PanNET have identified biallelic inactivation of MEN1 as the most common somatic mutation (40%), making Menin , a protein encoded by MEN1, an attractive therapeutic target [1][2] Germline mutations in MEN1 are associated with multiple neuroendocrine neoplasia syndrome, which is characterized by the occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (PanNET). In line with this, mice heterozygous for MEN1 (MEN1+/-) developed PanNET (Insulinoma)among others [10]. Pancreatic alpha-cell specific deletion of MEN1 in mouse resulted in Glucagonoma and Insulinoma [11][12]. However, among the MEN1 patients who develop PanNET, non-functional PanNET tumours account for the majority of the cases (51%) [14]. Therefore, developing MEN1 dependent, non-functional PanNET model will aid in better understanding of the disease. Previously, we have shown that pancreas specific expression of oncogene MYC develop PanNET tumours[16] and further characterization of these tumours revealed that they represent highly aggressive non-functional tumours. MYC target genes were one of the highly enriched pathways in the aggressive subtype of human PanNET[17]. Therefore, concurrent activation of MYC and loss of MEN1 specifically in the pancreas may accelerate the disease and serve as a model for MEN1-dependent non-functional PanNET. The majority of MEN1 mutations are inactivating mutations [18]. One potential strategy to target these loss of function mutations is to identify a vulnerability specific to MEN1-mutated cancer cells and exploit them therapeutically. One of the key functions of Menin is transcriptional regulation. It can repress transcription by interacting with transcriptional factors [19][20], or activate transcription by interacting with epigenetic regulators. Menin is found to be associated with Histone methyl transferases MLL1/MLL2 and methylate histone 3 on lysine 4 (H2K4me), a histone mark associated with transcriptional activation [21-23]. Menin has also been shown to interact with chromatin remodeller DAXX to facilitate repressive histone H3 lysine9 trimethylation mark [26]. Menin plays an important role in maintaining genome stability, particularly homologous recombination repair pathway[28-29]. Given Menin’s direct and indirect role in histone modifications and chromatin remodelling, loss of MEN1 could render cells dependent on alternative epigenetic regulators, and exploring this vulnerability could be an attractive treatment strategy. In addition to its role in transcriptional regulation, Menin has been shown to interact with various proteins to modulate cell signalling. For instance, Menin interacts with β-catenin and reduces its transcriptional activity (9). Beyond the Wnt signalling pathway, denovo pyrimidine synthesis, particularly the enzymes DHDOH and CAD were found to be synthetic lethal with MEN1 [33]. Advances in understanding of tumour progression revealed the importance of kinases to cancer cell growth and progression. To understand if any of the protein/lipid kinases exhibit synthetic lethality with MEN1, we have conducted a CRISPR based kinome-wide synthetic lethality screening in isogenic PanNET cancer cell line (BON1 MEN+/+ or BON1 MEN-/-). Through this approach, we have identified 18 synthetic lethal interactors including Wnt signalling modulators. The identification of kinases involved in Wnt pathway, which was previously shown to be synthetic lethal with MEN1, validates the robustness of our high throughput screen. In this proposal, we aim to validate the synthetic lethal interactor (Kinases and Chromatin modifiers) of MEN1 as a potential therapeutic target for PanNET and develop a mouse model for MEN1 associated PanNET.