Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma

Borgenvik, Anna; Holmberg, Karl O.; Bolin, Sara; Zhao, Miao; Savov, Vasil; Rosén, Gunnar; Hutter, Sonja; Garancher, Alexandra; Rahmanto, Aldwin Suryo; Bergström, Tobias; Olsen, Thale Kristin; Mainwaring, Oliver J.; Sattanino, Damiana; Verbaan, Annemieke D.; Rusert, Jessica M.; Sundström, Anders; Bravo, Mar Ballester; Dang, Yonglong; Wenz, Amelie S.; Richardson, Stacey; Fotaki, Grammatiki; Hill, Rebecca; Dubuc, Adrian M.; Kalushkova, Antonia; Remke, Marc; Čančer, Matko; Jernberg-Wiklund, Helena; Giraud, G; Chen, Xingqi; Taylor, Michael D.; Sangfelt, Olle; Clifford, Steven C.; Schüller, Ulrich; Wechsler‐Reya, Robert J.; Weishaupt, Holger; Swartling, Fredrik J.

doi:10.1158/0008-5472.can-22-2108

Cited by 12 publications

(13 citation statements)

References 51 publications

(103 reference statements)

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“…The presence of DTC in the bone marrow has also been shown to be associated with a higher risk of clinically detectable breast cancer metastasis [ 39 , 40 ]. A similar finding has also been reported in cancer patients with colon liver metastases [ 41 ] and MYC-amplified high-risk medulloblastoma [ 42 ]. In short, findings discussed here suggest that QCCs may exist earlier than relapse and play a key role in tumor recurrence.…”

Section: Quiescent Cancer Cells Lead To Tumor Recurrencesupporting

confidence: 86%

“…They identified a similar main quiescence-associated transcription program between both tumors that underlined an upregulation in stemness, pro-metastatic, chemoresistance, and EMT-like pathways, e.g., KLF4 and ZEB2 [ 44 ]. Moreover, in addition to ki67 and p27, researchers also consider other markers to focus on specific proportions of QCCs, e.g., Yes and YAP [ 41 ] or SOX9 [ 42 ], revealing the diversity of QCCs across different conditions (e.g., primary site, distant metastatic site, cancer type, or specific genomic signature).…”

Section: Quiescent Cancer Cells Lead To Tumor Recurrencementioning

confidence: 99%

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Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

Lindell

Zhong

Zhang

2023

IJMS

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Quiescent cancer cells (QCCs) are nonproliferating cells arrested in the G0 phase, characterized by ki67low and p27high. QCCs avoid most chemotherapies, and some treatments could further lead to a higher proportion of QCCs in tumors. QCCs are also associated with cancer recurrence since they can re-enter a proliferative state when conditions are favorable. As QCCs lead to drug resistance and tumor recurrence, there is a great need to understand the characteristics of QCCs, decipher the mechanisms that regulate the proliferative–quiescent transition in cancer cells, and develop new strategies to eliminate QCCs residing in solid tumors. In this review, we discussed the mechanisms of QCC-induced drug resistance and tumor recurrence. We also discussed therapeutic strategies to overcome resistance and relapse by targeting QCCs, including (i) identifying reactive quiescent cancer cells and removing them via cell-cycle-dependent anticancer reagents; (ii) modulating the quiescence-to-proliferation switch; and (iii) eliminating QCCs by targeting their unique features. It is believed that the simultaneous co-targeting of proliferating and quiescent cancer cells may ultimately lead to the development of more effective therapeutic strategies for the treatment of solid tumors.

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Section: Quiescent Cancer Cells Lead To Tumor Recurrencesupporting

confidence: 86%

Section: Quiescent Cancer Cells Lead To Tumor Recurrencementioning

confidence: 99%

Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

Lindell

Zhong

Zhang

2023

IJMS

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“…Conventional RNA sequencing was performed on GMYC ( n = 6) tumors that was compared to RNA sequences similarly generated on GTML ( n = 8) tumors 32 . When compared via cross-species analysis to other human childhood brain tumors, including glial or mixed glioneuronal tumors (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…Total RNA from GMYC ( n = 6) tumor samples was sequenced through the Ion Proton TM Sequencer at the Uppsala Genome Center, SciLifeLab, Uppsala University. Raw RNA-seq reads GMYC, previously generated GTML tumors ( n = 7) 32 and new GTML tumors and Arf knockout cell lines and controls were aligned to the mouse mm9 genome assembly using the STAR aligner (v2.7.2b) 71 followed by an additional application of Bowtie (v2.3.4.3) 72 . The STAR mapping utilized a two-pass approach, with the first alignment pass designed to discover splice junctions, which were then utilized for an improved alignment in the second pass.…”

Section: Methodsmentioning

confidence: 99%

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

et al. 2023

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Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.

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“…SOX9 is an important transcription factor located on chromosome 17q24. As a member of the SOX transcription factor family, SOX9 plays a key role in embryonic development and stem cell maintenance [3]. Shirian, et al veri ed that the protein level of SOX9 was up-regulated in 60 pairs of matched pituitary tumor tissues, and found that the high expression level of SOX9 was related to the invasive degree of growth hormone secreting pituitary adenoma patients and the formation of larger tumors [25].…”

Section: Discussionmentioning

confidence: 99%

Machine learning to comprehensively reveal signature genes and regulatory mechanisms in pituitary tumors

Wang¹,

Xiao²,

Xia³

2023

Preprint

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Background Pituitary tumors are among the rare tumors of the central nervous system. With advances in screening, the incidence of pituitary tumors is increasing every year. The symptoms of pituitary tumors are similar to those of some common diseases, and it is common to miss the diagnosis, which can lead to serious complications, affect life expectancy and quality of life, and lead to poor prognosis due to side effects of adjuvant chemotherapy and radiotherapy. Therefore, the search for new biomarkers is important for the early diagnosis and treatment .Methods Datasets related to pituitary tumors from the GEO database were collected and integrated, firstly, DEG screening and GO, KEGG and GSEA enrichment analysis were performed, then LASSO and SVM-RFE algorithms were used to identify pituitary tumor-related signature genes in the training set, and ROC performance and gene expression differences were verified in the test set. Based on this, the immune infiltration differences were analyzed, and the correlation between signature genes and immune cells was studied.Results We finally screened 6 signature genes, including CNTNAP2, LHX3, RAB11FIP3, SOX9, TBX19 and TGFBR, whose expression showed differences, and the expression of signature genes was correlated with tumor infiltrating immune cells abundance gene expression.Conclusion In this study, 6 signature genes were screened to contribute to the development of immune-targeted therapeutic agents for the early diagnosis of pituitary tumor patients.

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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma

Cited by 12 publications

References 51 publications

Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

Machine learning to comprehensively reveal signature genes and regulatory mechanisms in pituitary tumors

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