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Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy.

ABSTRACT: Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

SUBMITTER: Chung PED

PROVIDER: S-EPMC7156401 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Project description:Transcriptome analysis of mRNA samples from Rb/p53-deficient mouse pineoblastomas

2019-01-31 | GSE124537 | GEO

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Project description:Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

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Germ-line and somatic DICER1 mutations in pineoblastoma.

Project description:Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.

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Model-based analysis uncovers mutations altering autophagy selectivity in human cancer.

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Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption.

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A population-based analysis of germline BAP1 mutations in melanoma.

Project description:Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency?<0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma.

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Disruption of lysosome function promotes tumor growth and metastasis in Drosophila.

Project description:Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.

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Whole Exome Sequencing Uncovers Germline Variants of Cancer-Related Genes in Sporadic Pheochromocytoma.

Project description:Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic.Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic.About 50% of PCCs examined had somatic mutations on the known susceptibility VHL, NF1, and RET genes. In addition to these driver events, mutations on SYNE1, ABCC10, and RAD54B genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes.Additional somatic passenger mutations can be associated with known susceptibility VHL, NF1, and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.

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Project description:Aortic dissections associate with medial degeneration, thus suggesting a need to understand better the biophysical interactions between the cells and matrix that constitute the middle layer of the aortic wall. Here, we use a recently extended "Smoothed Particle Hydrodynamics" formulation to examine potential mechanisms of aortic delamination arising from smooth muscle cell (SMC) dysfunction or apoptosis, degradation of or damage to elastic fibers, and pooling of glycosaminoglycans (GAGs), with associated losses of medial collagen in the region of the GAGs. First, we develop a baseline multi-layered model for the healthy aorta that delineates medial elastic lamellae and intra-lamellar constituents. Next, we examine stress fields resulting from the disruption of individual elastic lamellae, lost SMC contractility, and GAG production within an intra-lamellar space, focusing on the radial transferal of loading rather than on stresses at the tip of the delaminated tissue. Results suggest that local disruptions of elastic lamellae transfer excessive loads to nearby intra-lamellar constituents, which increases cellular vulnerability to dysfunction or death. Similarly, lost SMC function and accumulations of GAGs increase mechanical stress on nearby elastic lamellae, thereby increasing the chance of disruption. Overall these results suggest a positive feedback loop between lamellar disruption and cellular dropout with GAG production and lost medial collagen that is more pronounced at higher distending pressures. Independent of the initiating event, this feedback loop can catastrophically propagate intramural delamination.

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