Cancer is a multi-stage disease caused by sequential mutations; however, the molecular mechanism generating cancer-initiating mutations for many cancers is not well understood. Using the developing cerebellum as model system, here we delineate a molecular mechanism for tumor initiation in medulloblastoma (MB), the most frequent malignant pediatric brain tumor. Activation of the Sonic hedgehog (SHH) pathway is frequent in MB, with mutations in the tumor suppressor PTCH1 (a negative regulator of SHH signaling) being the most common initiating event for SHH-MB. However, how SHH as a developmental mitogen promotes early carcinogenesis in the cells of origin, granule cerebellar progenitors (GCPs), remains to be determined. 
Here we report that physiological exposure of GCPs to Shh causes a distinct form of DNA replication stress, altering DNA replication dynamics to increase both origin firing and fork velocity. Shh promotes DNA helicase loading and activation in GCPs, with increased levels of Cdc7-dependent replication origin firing. S-phase duration is reduced and hyper-recombination consequently occurs. Such elevated recombination causes copy-number neutral LOH, an event seen frequently at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing in a MB mouse model is sufficient to reduce somatic recombination and preneoplastic tumor formation. We therefore establish that tissue-specific replication stress induced by Shh acts to promote LOH, which in tumor-prone Ptch1+/- GCPs can result in loss of this tumor suppressor, as an early cancer initiating event.


Sonic hedgehog causes replication stress promoting cancer initiation in medulloblastoma

"In this work, we present a viewpoint selection method specif-
ically designed for fibrous structures in a pre-operative context. A view
quality metric based on entropy was developed, which integrates the typ-
ical requirements of surgery planning. We applied our approach in the
case of cranial nerves surrounding skull base tumors. The relevance of the
viewpoints selected by our method was assessed qualitatively by a neu-
rosurgeon and quantitatively based on statistical tests. These viewpoints
were proven to have a high informative content, and therefore to enable a
good understanding and mental representation the 3D anatomical scene
in a pre-operative context."

Viewpoint selection for fibrous structures in a pre-operative context: application to cranial nerves surrounding skull base tumors

Glioblastoma (GBM) is one of the most aggressive malignant brain tumors, with a 5-year patient survival rate of 5% post diagnosis. Typically, magnetic resonance imaging (MRI) is used to identify tumor information to aid presurgical planning. Functional MRI (fMRI) is used in presurgical planning to identify eloquent areas of the cortex to avoid during surgery. Typical imaging captures the local tumor but fails to identify its global effects on cortical function, and we propose that fMRI can identify these effects. fMRI has identified resting state networks (RSN) throughout the brain relating to these global effects. Using fMRI data to guide GBM patient treatment, however, is difficult because GBM tumor mass distorts the cortex, making it difficult to know which RSNs are affected. However, unlike the cortex, the cerebellum is mostly unaffected in GBM and given its connections to the cortex, may provide a structurally-homogeneous framework to compare RSN changes across patients. Thus, we propose that by tracking changes in cerebellar networks, we can predict functional cortical effects by the tumor, allowing physicians to make more informed decisions on patient treatment. We organized the resting state fMRI data of 1000 healthy controls and 81 GBM patients into 280 regions of interest and assigned each region an RSN. We found consistent relationships between the within-network interhemispheric connectivity of the cortex and its cerebellar counterparts in controls, but this was altered in GBM patients. Network analysis has been used to investigate RSNs which revealed lower cerebellar global efficiency, modularity, and betweenness centrality in GBM patients. Our data suggest that GBM patients exhibit altered network architecture in the cerebellum and that GBMs disrupt functional connectivity between the cortex and cerebellum. Further analysis of cerebellar data in GBM patients could help localize the effects of cortical tumors on functional networks and improve pre-surgical planning.

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Sonic hedgehog causes replication stress promoting cancer initiation in medulloblastoma

Viewpoint selection for fibrous structures in a pre-operative context: application to cranial nerves surrounding skull base tumors

Using Cerebellar Data to Predict Cortical Changes in GBMs

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