Temporal profiling of therapy resistance in human medulloblastoma identifies novel targetable drivers of recurrence

Bakhshinyan, David; Adile, Ashley; Liu, Jeff; Gwynne, William D.; Suk, Yujin; Custers, Stefan; Burns, Ian; Singh, Mohini; McFarlane, Nicole; Subapanditha, Minomi; Qazi, Maleeha; Vora, Parvez; Kameda-Smith, Michelle; Savage, Neil; Desmond, Kim L; Tatari, Nazanin; Tran, Damian; Seyfrid, Mathieu; Hope, Kristin J.; Bock, Nicholas A.; Venugopal, Chitra; Bader, Gary D.; Singh, Sheila K.

doi:10.1126/sciadv.abi5568

Cited by 11 publications

(13 citation statements)

References 43 publications

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“…CSCs have been identified in many types of brain tumors, including glioblastoma (GBM) and MB; they are able to self-renew under clonal conditions, and differentiate into neuron- and glia-like cells as well as into atypical cells with mixed phenotypes ( Singh et al, 2004 ). Many findings suggest that enriched, treatment-resistant subpopulations of CSCs are involved in driving MB tumor recurrence and metastasis subsequent to standard treatment ( Sun et al, 2017 ; Bakhshinyan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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Tumor-specific alterations in metabolism have been recognized to sustain the production of ATP and macromolecules needed for cell growth, division and survival in many cancer types. However, metabolic heterogeneity poses a challenge for the establishment of effective anticancer therapies that exploit metabolic vulnerabilities. Medulloblastoma (MB) is one of the most heterogeneous malignant pediatric brain tumors, divided into four molecular subgroups (Wingless, Sonic Hedgehog, Group 3 and Group 4). Recent progresses in genomics, single-cell sequencing, and novel tumor models have updated the classification and stratification of MB, highlighting the complex intratumoral cellular diversity of this cancer. In this review, we emphasize the mechanisms through which MB cells rewire their metabolism and energy production networks to support and empower rapid growth, survival under stressful conditions, invasion, metastasis, and resistance to therapy. Additionally, we discuss the potential clinical benefits of currently available drugs that could target energy metabolism to suppress MB progression and increase the efficacy of the current MB therapies.

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Section: Introductionmentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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“…D425-Med (D425, RRID: CVCL_1275) [ 33 ], a treatment-naïve MB cell line, was propagated in high glucose Dulbecco’s Modified Eagle Medium (DMEM, Life Technologies# 11965-118) supplemented with 1% penicillin–streptomycin, and 20% FBS. The matched recurrent versions of D425, HD-MB03 and SU_MB002 were generated through the established, previously published in vivo treatment protocol [ 22 ]. Human fetal neural stem cells (hNSCs) were isolated using a previously described protocol [ 34 ] and cultured in NCC media.…”

Section: Methodsmentioning

confidence: 99%

“…In this work, we leveraged our established therapy-adapted patient-derived xenograft model of Group 3 MB progression [ 22 ] combined with N-glycocapture profiling to investigate changes in expression of surface proteins through tumor engraftment, regression, and recurrence. Label-free quantification of MB samples isolated from brains of mice undergoing chemoradiotherapy led to the identification of 23 proteins that were highly expressed (log10 fold-change > 5) in relapse when compared to the samples isolated at engraftment and untreated controls.…”

Section: Introductionmentioning

confidence: 99%

Dynamic profiling of medulloblastoma surfaceome

Bakhshinyan,

Suk,

Kuhlmann

et al. 2023

acta neuropathol commun

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Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the four distinct molecular subgroups, Group 3 and 4 have the poorest patient outcomes due to the aggressive nature of the tumor and propensity to metastasize and recur post therapy. The toxicity of the SOC and lack of response in specific subtypes to the SOC underscores the urgent need for developing and translating novel treatment options including immunotherapies. To identify differentially enriched surface proteins that could be evaluated for potential future immunotherapeutic interventions, we leveraged N-glycocapture surfaceome profiling on Group 3 MB cells from primary tumor, through therapy, to recurrence using our established therapy-adapted patient derived xenograft model. Integrin 𝛼5 (ITGA5) was one of the most differentially enriched targets found at recurrence when compared to engraftment and untreated timepoints. In addition to being enriched at recurrence, shRNA-mediated knockdown and small molecule inhibition of ITGA5 have resulted in marked decrease in proliferation and self-renewal in vitro and demonstrated a survival advantage in vivo. Together, our data highlights the value of dynamic profiling of cells as they evolve through therapy and the identification of ITGA5 as a promising therapeutic target for recurrent Group 3 MB.

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“…To assess the clinical implications of utilizing IACS-010759 to treat G3 MB tumors, we implemented a pre-clinical orthotopic intracerebellar xenograft mouse model. The HD-MB03 G3 MB line is a well-established xenograft model for studying highly aggressive G3 MB tumors in vivo 24 , 46 , 47 . When transplanted into the brains of NOD-SCID gamma (NSG) mice, HD-MB03 cells develop tumors that resemble the large-cell/anaplastic (LCA) histomorphology, with numerous mitoses and apoptotic bodies, commonly exhibited in many G3 MB patient tumors (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma

et al. 2023

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Group 3 medulloblastoma (G3 MB) carries the worst prognosis of all MB subgroups. MYC oncoprotein is elevated in G3 MB tumors; however, the mechanisms that support MYC abundance remain unclear. Using metabolic and mechanistic profiling, we pinpoint a role for mitochondrial metabolism in regulating MYC. Complex-I inhibition decreases MYC abundance in G3 MB, attenuates the expression of MYC-downstream targets, induces differentiation, and prolongs male animal survival. Mechanistically, complex-I inhibition increases inactivating acetylation of antioxidant enzyme SOD2 at K68 and K122, triggering the accumulation of mitochondrial reactive oxygen species that promotes MYC oxidation and degradation in a mitochondrial pyruvate carrier (MPC)-dependent manner. MPC inhibition blocks the acetylation of SOD2 and oxidation of MYC, restoring MYC abundance and self-renewal capacity in G3 MB cells following complex-I inhibition. Identification of this MPC-SOD2 signaling axis reveals a role for metabolism in regulating MYC protein abundance that has clinical implications for treating G3 MB.

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Temporal profiling of therapy resistance in human medulloblastoma identifies novel targetable drivers of recurrence

Abstract: Gene expression profiling of medulloblastoma cells undergoing therapy identifies BPIFB4 as a novel target for recurrent disease.

Cited by 11 publications

References 43 publications

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Dynamic profiling of medulloblastoma surfaceome

Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma

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