Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Chung, Philip E.D.; Gendoo, Deena M.A.; Ghanbari-Azarnier, Ronak; Liu, Jeff C.; Jiang, Zhe; Tsui, Jennifer; Wang, Dong‐Yu; Xiao, Xiao; Li, Bryan; Dubuc, Adrian M.; Shih, David; Remke, Marc; Ho, Ben; Garzia, Livia; Ben‐David, Yaacov; Kang, Seok‐Gu; Croul, Sidney; Haibe‐Kains, Benjamin; Huang, Annie; Taylor, Michael D.; Zacksenhaus, Eldad

doi:10.1038/s41467-020-15585-2

Cited by 24 publications

(26 citation statements)

References 70 publications

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“…Recent studies revealed the potential therapeutic target against DICER1 ‐mutant malignancies. Chung et al 19 . reported that nortiptyline (tricyclic antidepressant) effectively suppress the growth of pineoblastoma in DICER1 ‐deleted mouse model and pineoblastoma cell line TS13‐19.…”

Section: Discussionmentioning

confidence: 99%

An autopsy case of prostatic rhabdomyosarcoma with DICER1 hotspot mutation

Miyama

Makise

Miyakawa

et al. 2020

Pathology International

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Somatic hotspot DICER1 mutations, which frequently coexist with germline inactivating mutation (i.e., DICER1 syndrome), have been identified in various types of benign and malignant conditions. Herein, we report an autopsy case of prostatic rhabdomyosarcoma (RMS) with a hotspot DICER1 c.5125G>A (p.D1709N) mutation. A 26 year‐old man presented with a prostatic mass, hematuria, and urinary retention. He underwent total pelvic exenteration, colostomy, ileal conduit construction and partial urethrectomy. Five months postoperatively, he developed multiple metastases to the lungs, brain, iliopsoas muscles and bones. He died of respiratory failure, and autopsy was performed. Microscopically, the tumor was primarily composed of uniform primitive mesenchymal cells infiltrating to the prostate with cambium layer. Rhabdomyoblasts and anaplastic cells were focally observed. Immunohistochemically, tumor cells were positive for desmin, myogenin, PAX7, HMGA2. Multinodular goiter was detected at autopsy. Because the morphology is similar to pleuropulmonary blastoma and DICER1‐mutant RMS of the female genital tract, we tested and identified a hotspot DICER1 mutation with Sanger sequencing. Recognizing DICER1‐mutant tumor is important because of its frequent association with germline DICER1 inactivation and potential therapeutic implication. Further research is needed to clarify whether this case can be classified as embryonal RMS with anaplasia or ‘DICER1‐associated sarcoma’.

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Section: Discussionmentioning

confidence: 99%

An autopsy case of prostatic rhabdomyosarcoma with DICER1 hotspot mutation

Miyama

Makise

Miyakawa

et al. 2020

Pathology International

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“…Denatured proteins were separated on a 15% acrylamide gel and then transferred to a PVDF membrane. After blocking with 5% dry skim milk in PBST, blots were incubated with Abs against ATG5 (Novus Biologicals) 59 , p62 (Abnova) 60 , LC3 (Nanotools) 61 , and β-actin (Sigma-Aldrich) 62 . Immunocomplexes were then labelled with a HRP-conjugated anti-mouse, or with anti-rabbit antibodies, and visualised using ECL Prime Western Blotting Detection Reagent (GE Healthcare) with an ImageQuant LAS 4000 (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner

Nomura

Ito

Ooshio

et al. 2021

Sci Rep

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Autophagy is a cellular degradation system contributing to homeostasis of tissue stem cells including haematopoietic stem cells (HSCs). It plays pleiotropic roles in HSC characteristics throughout life, but its stage-specific roles in HSC self-renewal are unclear. To investigate the effects of Atg5 deletion on stage-specific HSC functions, we compared the repopulating capacity of HSCs in Atg5f/f;Vavi-cre mice from postnatal day (P) 0–7 weeks of age. Interestingly, Atg5 deficiency led to no remarkable abnormality in the HSC self-renewal capacity at P0, but significant defects at P7, followed by severe defects. Induction of Atg5 deletion at P5 by tamoxifen administration to Atg5f/f;Rosa26-Cre-ERT2 mice resulted in normal haematopoiesis, including the HSC population, until around 1 year, suggesting that Atg5 in the early neonatal period was critical for haematopoiesis in adults. Mitochondrial oxidative stress was increased by Atg5 loss in neonatal HSC/progenitor cells. Although p62 had accumulated in immature bone marrow cells of Atg5f/f;Vavi-cre mice, p62 deletion did not restore defective HSC functions, indicating that Atg5-dependent haematopoietic regulation in the developmental period was independent of p62. This study proposes a critical role of autophagy in HSC protection against harsh environments in the early neonatal stage, which is essential for healthy long-term haematopoiesis.

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“…Similar therapies combining checkpoint control inhibitors with other vulnerabilities in the TME or the metastatic cascade may offer even better outcomes. The generation of immune-competent mouse models that develop macroscopic metastases (e.g., [ 68 , 69 ]), provide powerful platforms to study metastasis and assess potential new drug combinations that target both the tumor and TME [ 70 ].…”

Section: The Tumor Microenvironmentmentioning

confidence: 99%