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  • 1. Blixt, Maria
    et al.
    Hellsand, Minas
    Konjusha, Dardan
    Zhang, Hanzhao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Hallböök: Stamceller, retinal utveckling och regeneration.
    Stenfelt, Sonya
    Åkesson, Mikael
    Rafati, Nima
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tararuk, Tatsiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Hallböök: Stamceller, retinal utveckling och regeneration.
    All-Eriksson, Charlotta
    Ring, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Hallböök: Stamceller, retinal utveckling och regeneration.
    Hallböök, Finn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Hallböök: Stamceller, retinal utveckling och regeneration.
    MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma2022Inngår i: Oncogenesis, E-ISSN 2157-9024, Vol. 11, nr 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Retinoblastoma is a rare, intraocular paediatric cancer that originates in the neural retina and is most frequently caused by bi-allelic loss of RB1 gene function. Other oncogenic mutations, such as amplification and increased expression of the MYCN gene, have been found even with proficient RB1 function. In this study, we investigated whether MYCN over-expression can drive carcinogenesis independently of RB1 loss-of-function mutations. The aim was to elucidate the events that result in carcinogenesis and identify the cancer cell-of-origin. We studied the chicken retina, a well-established model for studying retinal neurogenesis, and generated over-expression of MYCN by in ovo electroporation. In parallel, we established an equivalent human stem cell-derived retinal organoid (retinoid) model system. We found that over-expression of MYCN induced tumorigenic growth with high frequency in RB1-proficient chicken retinas and human retinoids. In both systems, the tumorigenic cells expressed markers for undifferentiated cone photoreceptor/horizontal cell progenitors. The over-expression resulted in metastatic retinoblastoma within 7-9 weeks in chicken. MYCN cells could be grown in vitro and, when orthotopically injected, formed tumours that infiltrated the sclera and optic nerve and expressed markers for undifferentiated cones. Investigation of the tumour cell phenotype determined that the potential for neoplastic growth was embryonic stage-dependent and featured a cell-specific resistance to apoptosis in the cone/horizontal cell lineage, but not in ganglion or amacrine cells. We conclude that MYCN over-expression is sufficient to drive tumorigenesis and that a cell-specific resistance to apoptosis in the cone/horizontal cell lineage mediates the cancer phenotype.

    Fulltekst (pdf)
    fulltext
  • 2.
    Gonzalez-Rodriguez, Patricia
    et al.
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Engskog-Vlachos, Pinelopi
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Zhang, Hanzhao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Hallböök: Stamceller, retinal utveckling och regeneration. Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Murgoci, Adriana-Natalia
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Zerdes, Ioannis
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.
    Joseph, Bertrand
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG122020Inngår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 11, artikkel-id 69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5-ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12-dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

    Fulltekst (pdf)
    FULLTEXT01
  • 3.
    Zhang, Hanzhao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi och neurodegeneration.
    Role of MYCN in retinoblastoma: From carcinogenesis to tumor progression2024Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Retinoblastoma, a pediatric malignancy of the retina, is primarily driven by the bi-allelic inactivation of the RB1gene. However, a subset of cases are characterized by proficient RB1 functions but with MYCN copy number mutations, suggesting an alternative oncogenic mechanism in the absence of RB1 mutations. The aim of this thesis is to investigate the intricate molecular and cellular pathways implicated in retinoblastoma, with a particular focus on the role of MYCN expression and its interplay with the cell cycle and apoptotic pathways.

    In Paper I, we explored the regulatory mechanisms underpinning MYCN-induced retinoblastoma using aRB1-proficient MYCN-overexpressing in vivo model in embryonic chicken retina and MYCN-transformed cells in culture. Our findings revealed that MYCN overexpression led to a significant upregulation of E2F levels, thereby dysregulating the cell cycle and mimicking the mechanistic phenotype of RB1-deficient tumors. Inhibition on E2f DNA-binding activity efficiently normalized growth and apoptosis in MYCN-transformed cells in culture. Despite RB1 proficiency, the elevated E2F levels induced a neoplastic behavior in retinal cells, indicating a novel mechanism of retinoblastoma carcinogenesis independent of RB1 inactivation.

    Paper II employed single-cell RNA sequencing to dissect the cellular composition of MYCN-driven retinoblastoma in chicken in vivo model, revealing a predominant origin in cone photoreceptor progenitors. This finding suggested a cell-type-specific vulnerability to MYCN-induced transformation. The research further identifies a notable heterogeneity within the MYCN-transformed cells, with a subset of cells exhibiting non-cone photoreceptor features but features of other neurons like ganglion cells. A cluster was also identified withelevated expression of genes related to malignancy and tumor progression, including UBE2C and TOP2A. This suggested a link between MYCN overexpression and tumor development, potentially mediated through the E2F pathway.

    In Paper III, the focus shifted to the interplay between MYCN expression, E2f activity, and the p53 pathway in human retinoblastoma cell lines exhibiting both RB1 deficiency and MYCN amplification. By modulating E2f and p53 pathway activities using chemical inhibitors, we demonstrated the essential role of MYCN expression level in mediating p53-driven growth inhibition and highlighted the independent effects of E2f inhibition and p53 activation by a Mdm2 inhibitor.

    Together, these studies illuminate the intricate molecular pathways involved in MYCN-amplified retinoblastoma, emphasizing the pivotal role of MYCN in disrupting cell cycle regulation and promoting tumorigenesis. These insights not only advance our understanding of retinoblastoma pathogenesis but also provide potential therapeutic targets within the MYCN-E2F axis, offering novel treatment strategies in MYCN-amplified retinoblastoma.

    Delarbeid
    1. Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.
    Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.
    Vise andre…
    2023 (engelsk)Inngår i: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
    Abstract [en]

    PURPOSE: Retinoblastoma, a childhood cancer, is most frequently caused by bi-allelic inactivation of RB1 gene. However, other oncogenic mutations such as MYCN amplification can induce retinoblastoma with proficient RB1. Previously, we established RB1-proficient MYCN-overexpressing retinoblastoma models both in human organoids and chicken. Here, we investigate the regulatory events in MYCN-induced retinoblastoma carcinogenesis based on the model in chicken.

    METHODS: MYCN transformed retinal cells in culture were obtained from in vivo MYCN electroporated chicken embryo retina. The expression profiles were analysed by RNA sequencing. Chemical treatments, qRT-PCR, flow cytometry, immunohisto- and immunocytochemistry and western blot were applied to study the properties and function of these cells.

    RESULTS: The expression profile of MYCN-transformed retinal cells in culture showed cone photoreceptor progenitor signature and robustly increased levels of E2Fs. This expression profile was consistently observed in long-term culture. Chemical treatments confirmed RB1 proficiency in these cells. The cells were insensitive to p53 activation but inhibition of E2f efficiently induced cell cycle arrest followed by apoptosis.

    CONCLUSION: In conclusion, with proficient RB1, MYCN-induced high level of E2F expression dysregulates the cell cycle and contributes to retinoblastoma carcinogenesis. The increased level of E2f renders the cells to adopt a similar mechanistic phenotype to a RB1-deficient tumour.

    Emneord
    Animal model, Chicken, E2F, Intraocular cancer, MYCN, RB1 proficient, Retinoblastoma
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-522867 (URN)10.1007/s13402-023-00863-0 (DOI)37606819 (PubMedID)
    Tilgjengelig fra: 2024-02-12 Laget: 2024-02-12 Sist oppdatert: 2024-02-21
    2. Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retina
    Åpne denne publikasjonen i ny fane eller vindu >>Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retina
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-523113 (URN)
    Tilgjengelig fra: 2024-02-14 Laget: 2024-02-14 Sist oppdatert: 2024-02-21
    3. Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activity
    Åpne denne publikasjonen i ny fane eller vindu >>Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activity
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-523107 (URN)
    Tilgjengelig fra: 2024-02-14 Laget: 2024-02-14 Sist oppdatert: 2024-02-21
    Fulltekst (pdf)
    UUThesis_H-Zhang-2024
    Download (jpg)
    preview image
  • 4. Zhang, Hanzhao
    et al.
    Konjusha, Dardan
    Rafati, Nima
    Tararuk, Tatsiana
    Hallböök, Finn
    Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.2023Inngår i: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Retinoblastoma, a childhood cancer, is most frequently caused by bi-allelic inactivation of RB1 gene. However, other oncogenic mutations such as MYCN amplification can induce retinoblastoma with proficient RB1. Previously, we established RB1-proficient MYCN-overexpressing retinoblastoma models both in human organoids and chicken. Here, we investigate the regulatory events in MYCN-induced retinoblastoma carcinogenesis based on the model in chicken.

    METHODS: MYCN transformed retinal cells in culture were obtained from in vivo MYCN electroporated chicken embryo retina. The expression profiles were analysed by RNA sequencing. Chemical treatments, qRT-PCR, flow cytometry, immunohisto- and immunocytochemistry and western blot were applied to study the properties and function of these cells.

    RESULTS: The expression profile of MYCN-transformed retinal cells in culture showed cone photoreceptor progenitor signature and robustly increased levels of E2Fs. This expression profile was consistently observed in long-term culture. Chemical treatments confirmed RB1 proficiency in these cells. The cells were insensitive to p53 activation but inhibition of E2f efficiently induced cell cycle arrest followed by apoptosis.

    CONCLUSION: In conclusion, with proficient RB1, MYCN-induced high level of E2F expression dysregulates the cell cycle and contributes to retinoblastoma carcinogenesis. The increased level of E2f renders the cells to adopt a similar mechanistic phenotype to a RB1-deficient tumour.

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