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Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

ABSTRACT: Most human cancers arise from stem/progenitor cells by sequential accumulation of genetic/epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here we show that a single p53 mutation, despite causing no defect in mouse brain, promoted neural stem/progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas/glioblastomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem-cell niche. Unexpectedly, Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53-mutant Sonic Hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and developing brain, promoting malignant gliomas/glioblastoma and suppressing SHH-medulloblastoma formation, respectively.

ORGANISM(S): Mus musculus

PROVIDER: GSE115840 | GEO | 2021/06/15

REPOSITORIES: GEO

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Rictor/mTORC2 signaling has opposing functions in adult glioma and childhood SHH medulloblastoma

Project description:Primary glioblastoma, representing over 90% of adult glioblastoma, develop rapidly without preexisting lower-grade glioma. We have generated a mouse model of primary glioblastoma driven by a single p53 mutation. These p53-mutant gliomas lose the syntenic region of human chromosome 10q, which is mapped to mouse chr19 and chr7. Loss of mouse chr19, containing Pten, activates PI3K/Akt signaling. Rictor/mTORC2 deletion inhibits Akt signaling, causing a significant delay in p53-mutant driven glioma formation. Unexpectedly, Rictor/mTORC2 loss promotes p53-mutant driven medulloblastomas with unique features of pediatric SHH medulloblastoma. Mechanistically, Rictor/mTORC2 loss inhibits the generation of glioma precursor cells from neural stem/progenitor cells in the adult brain, while causing a delay in differentiation of granule cell precursors in the developing brain, a cell-of-origin of SHH medulloblastoma.

2018-06-01 | GSE78895 | GEO

Mus musculus

Project description:Rictor/mTORC2 signaling has opposing functions in adult glioma and childhood SHH medulloblastoma

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Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

Project description:Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

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Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma (EdU-Seq)

Project description: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.

2020-07-20 | GSE147409 | GEO

Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma (RNA-Seq)

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Transcriptome analysis of medulloblastoma tumors in mice

Project description:The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally-stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem and forebrain. Transplantation of Nmyc WT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating SHH-dependence and SHH-independence, respectively. These differences were regulated in-part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal. 9 (total) orthotopic tumors generated from E16C, P0C, and P0F NSCs transduced with a mutation-stabilized N-Myc were compared to transduced (but not transplanted) NSCs, NSCs transduced with GFP, and cells derived from the orthotopic tumors. These were also compared to 5 normal P7 cerebella, and 32 medulloblastoma tumors from the GTML mouse model. A cell line derived from a tumor from the GTML mouse model is also included in the comparison.

2012-03-20 | E-GEOD-36594 | biostudies-arrayexpress

Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure

Project description:The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to regulating glucose and lipid metabolism. In the perivascular adipose tissue (PVAT) mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (RictoraP2KO) mice generated by using adipocyte protein-2 gene promoter-driven CRE recombinase to delete Rictor. 24 hour mean arterial pressure (MAP) was increased in RictoraP2KO mice, and the physiologic decline in MAP during the dark period impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides (NPs) and NP receptor expression in adipocytes. Moreover, clock gene expression was dampened or phase-shifted in PVAT. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus (SCN), though Rictor gene expression was also lower in brain of RictoraP2KO mice. Thus, the present study underscores the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes and brain to tune physiological outcomes such as blood pressure and locomotion. Gene expression in PVAT of RictoraP2KO mice was compared to controls (Rictorfl/fl) mice.

2015-07-05 | E-GEOD-67077 | biostudies-arrayexpress

Transcriptome analysis of medulloblastoma tumors in mice

2012-03-20 | GSE36594 | GEO

The lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation

Project description:The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location since SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of Smo (SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres with SmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high level SHH signaling compared to GCPs in the medial cerebellum (vermis), as more SmoM2 or Ptch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide new insights into intrinsic differences within GCPs that impact on SHH-MB progression.

2018-02-22 | GSE110932 | GEO

Expression data from mouse model using targeted deletion of hepatic RICTOR (Albumin-Cre Rictor LoxP/LoxP)

Project description:Recent work using mouse models has revealed that mTORC2, which unlike mTORC1 is not acutely sensitive to rapamycin, plays a key role in the regulation of organismal physiology. The substrates and pathways regulated by mTORC2 are at present relatively unknown Using a mouse model with a targeted deletion of hepatic RICTOR, we investigated the loss of mTORC2 on the murine liver transcriptome Rictor floxed (RKO) and control mice (n=4 per group) were fasted overnight, refed for 3 hr, then sacrificed. Livers were removed, rinsed in PBS, and flash frozen in liquid nitrogen. RNA was extracted and hybridized to Affymetrix Genechip Mouse Gene 1.0 ST arrays

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