Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling

Nazio, Francesca; Pò, Agnese; Abballe, Luana; Ballabio, Claudio; Camassei, Francesca Diomedi; Bordi, Matteo; Camera, Antonio; Caruso, Simona; Caruana, Ignazio; Pezzullo, Marco; Ferraina, Caterina; Milletti, Giacomo; Gianesello, Matteo; Reddel, Sofia; Compagnucci, Luca; Ceglie, Donatella; Marinelli, Sara; Campello, Silvia; Papaleo, Elena; Miele, Evelina; Cacchione, Antonella; Carai, Andrea; Vinci, Maria; Velardi, Enrico; Angelis, Biagio De; Tiberi, Luca; Quintarelli, Concetta; Mastronuzzi, Angela; Ferretti, Elisabetta; Locatelli, Franco; Cecconi, Francesco

doi:10.1007/s00401-021-02347-7

Cited by 30 publications

(22 citation statements)

References 103 publications

(165 reference statements)

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“… 15 , 16 In addition, recent findings highlighted an important involvement of Ambra1 in cell cycle regulation, in particular controlling the abundance of D‐type cyclins. 28 ,S1,S19 These findings, together with the identification of a c‐Myc/Ambra1/STAT3 oncogenic pathway, 29 pointed at cancer as one major field of study for Ambra1.…”

Section: Discussionmentioning

confidence: 99%

Ambra1 deficiency impairs mitophagy in skeletal muscle

Gambarotto

Metti

Chrisam

et al. 2022

J cachexia sarcopenia muscle

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Background Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency. Methods To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1 fl/fl :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux. Results Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3-and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle. Conclusions Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.

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Section: Discussionmentioning

confidence: 99%

Ambra1 deficiency impairs mitophagy in skeletal muscle

Gambarotto

Metti

Chrisam

et al. 2022

J cachexia sarcopenia muscle

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“…[31,32] However, the function of autophagy in the stemness phenotype is paradoxical, as autophagy plays a dual role in cancer. [6] On the one hand, autophagy sustains the self-renewal and therapy resistance of cancer stem cells; [33,34] on the other hand, loss of autophagy impedes stem cell differentiation and increases tumorigenicity. [35] In glioma stem cells, diverse inducer-mediated autophagy plays distinct roles.…”

Section: Discussionmentioning

confidence: 99%

ASCL2 Maintains Stemness Phenotype through ATG9B and Sensitizes Gliomas to Autophagy Inhibitor

et al. 2022

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Autophagy is a highly conserved process that is vital for tumor progression and treatment response. Although autophagy is proposed to maintain the stemness phenotype in adult diffuse glioma, the molecular basis of the link between autophagy and stemness is poorly understood, which makes it impossible to effectively screen for the population that will benefit from autophagy‐targeted treatment. Here, ATG9B as essential for self‐renewal capacity and tumor‐propagation potential is identified. Notably, ASCL2 transcriptionally regulates the expression of ATG9B to maintain stemness properties. The ASCL2‐ATG9B axis is an independent prognostic biomarker and indicator of autophagic activity. Furthermore, the highly effective blood–brain barrier (BBB)‐permeable autophagy inhibitor ROC‐325, which can significantly inhibit the progression of ASCL2‐ATG9B axisHigh gliomas as a single agent is investigated. These data demonstrate that a new ASCL2‐ATG9B signaling axis is crucial for maintaining the stemness phenotype and tumor progression, revealing a potential autophagy inhibition strategy for adult diffuse gliomas.

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“…Finally, it has been demonstrated that autophagy positively regulates stemness in MB cells. Indeed, the expression of the pro-autophagy factor AMBRA1 depends on c-MYC levels, and it is strongly upregulated in Group 3 MB-CSCs[ 58 ].…”

Section: Metabolic Features Of Mb Cancer (Stem) Cellsmentioning

confidence: 99%

“…Moreover, IP6 synergised with Cisplatin, potentiating its cytotoxic activity in vitro and in vivo, and extending survival of the mice[ 55 ] significantly. Finally, pharmacological inhibition of the pro-autophagy factor AMBRA1 affected both the growth and invasion potential of group 3 MB-CSCs profoundly, enhanced by the combination of AMBRA1 and STAT3 inhibition[ 58 ].…”

Section: Targeted Therapies In Mbmentioning

confidence: 99%

Metabolic determinants of stemness in medulloblastoma

Martín-Rubio¹,

Espiau-Romera²,

Royo-García³

et al. 2022

WJSC

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Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glut athione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.

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Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling

Cited by 30 publications

References 103 publications

Ambra1 deficiency impairs mitophagy in skeletal muscle

Ambra1 deficiency impairs mitophagy in skeletal muscle

ASCL2 Maintains Stemness Phenotype through ATG9B and Sensitizes Gliomas to Autophagy Inhibitor

Metabolic determinants of stemness in medulloblastoma

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