Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance

Abstract

The identification of key tumorigenic events in Sonic Hedgehog subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH-pathway mutations, recent genome-wide sequencing studies have not revealed commonly-mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH–associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 WNT, 44 Group 3, 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor (GNP) germinal zone exit and migration initiation in an ex vivo model of early post-natal cerebellar development. These findings establish VAV1 as a critical epigenetically-regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.

Vav1: A Dr. Jekyll and Mr. Hyde protein - good for the hematopoietic system, bad for cancer

“…Fernandez-Zapico, et al ., demonstrated that epigenetic changes in the Vav1 gene, but not gene amplification, contributed to its aberrant expression in pancreatic cancer cell lines [ 69 ]. These results are further substantiated by a recent report indicating that Vav1 was identified by cross-species epigenetics to play a critical role in maintenance of Sonic Hedgehog (SHH) subgroup medulloblastoma tumors (MBSHH) [ 74 ]. This study identified widespread hypo-methylation of Vav1, leading to its elevated expression, as a conserved aberrant epigenetic event that characterizes the majority of MBSHH tumors and is associated with poor outcome in MBSHH patients.…”

“…Several melanoma cell lines also express wild-type Vav1, including the highly metastatic BLM cells, although the level of protein expression was low and it was localized in the cell periphery near the plasma membrane [ 73 ]. Finally, a large screen of medulloblastomas identified widespread expression of Vav1 in the majority of specimens analyzed and Vav1 was demonstrated to play a critical role in medulloblastoma tumor maintenance, with Vav1 abrogation markedly reducing medulloblastoma growth [ 74 ].…”

“…This study identified widespread hypo-methylation of Vav1, leading to its elevated expression, as a conserved aberrant epigenetic event that characterizes the majority of MBSHH tumors and is associated with poor outcome in MBSHH patients. These findings establish Vav1 as an epigenetically regulated oncogene with a key role in MBSHH maintenance [ 74 ].…”

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…Moreover, demethylation of VAV1 in the promoter region was shown to increase Vav1 expression in pancreatic cancer, and targeting Vav1 inhibited pancreatic cancer metastasis (Fernandez-zapico et al, 2005;Razidlo et al, 2015). Similarly, VAV1 gene is hypomethylated in medulloblastoma, leading to increased expression of Vav1 protein, which was correlated with the proto-oncogene MYCN amplification (Lindsey et al, 2014). Therefore, there is a need to elucidate epigenetic mechanisms regulating Vav expression, which can lead to novel therapeutic strategies.…”

Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

“…Several recent studies have indicated that mutations in various domains of the Vav1 protein are present in human cancers such as adult T-cell leukemia/lymphoma (Kataoka et al, 2015), lung adenocarcinoma and squamous cell carcinomas (Campbell et al, 2016), and peripheral T-cell lymphomas (Abate, da Silva-Almeida et al, 2017). In addition, numerous studies have reported the unexpected expression of Vav1, normally found only in the hematopoietic system, in a variety of human cancers, such as neuroblastoma (Hornstein et al, 2003), lung (Lazer et al, 2009), breast (Lane et al, 2008;Sebban et al, 2013;Du et al, 2014;Grassilli et al, 2014), ovarian (Wakahashi et al, 2013), prostate (Kniazev Iu et al, 2003), esophageal (Zhu et al, 2017), and brain tumors (Lindsey et al, 2014). Notably, Vav1 expression was also identified in more than 50% of 95 examined pancreatic ductal adenocarcinoma (PDAC) tumor specimens (Fernandez-Zapico et al, 2005), a finding that was validated by Huang et al (2016).…”