Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 10
  • Item
    Thumbnail Image
    Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and Pten loss
    Mejia-Hernandez, JO ; Keam, SP ; Saleh, R ; Muntz, F ; Fox, SB ; Byrne, D ; Kogan, A ; Pang, L ; Huynh, J ; Litchfield, C ; Caramia, F ; Lozano, G ; He, H ; You, JM ; Sandhu, S ; Williams, SG ; Haupt, Y ; Haupt, S (SPRINGERNATURE, 2022-09-08)
    Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including immunotherapies. Our prostate cancer models strongly support the role of tumour suppressor p53 in functioning to critically restrain the emergence of cancer pathways that drive cell cycle progression; alter metabolism and vasculature to fuel tumour growth; and mediate epithelial to mesenchymal-transition, as vital to invasion. Importantly, we also discovered that the type of p53 alteration dictates the specific immune cell profiles most significantly disrupted, in a temporal manner, with ramifications for disease progression. These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.
  • Item
    Thumbnail Image
    Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status
    Mejia-Hernandez, JO ; Raghu, D ; Caramia, F ; Clemons, N ; Fujihara, K ; Riseborough, T ; Teunisse, A ; Jochemsen, AG ; Abrahmsen, L ; Blandino, G ; Russo, A ; Gamell, C ; Fox, SB ; Mitchell, C ; Takano, EA ; Byrne, D ; Miranda, PJ ; Saleh, R ; Thorne, H ; Sandhu, S ; Williams, SG ; Keam, SP ; Haupt, Y ; Haupt, S (MDPI, 2022-08-01)
    Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.
  • Item
    Thumbnail Image
    MDM4 is a rational target for treating breast cancers with mutant p53
    Miranda, PJ ; Buckley, D ; Raghu, D ; Pang, J-MB ; Takano, EA ; Vijayakumaran, R ; Teunisse, AFAS ; Posner, A ; Procter, T ; Herold, MJ ; Gamell, C ; Marine, J-C ; Fox, SB ; Jochemsen, A ; Haupt, S ; Haupt, Y (WILEY, 2017-04-01)
  • Item
    Thumbnail Image
    An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy
    Zhang, AY ; Chiam, K ; Haupt, Y ; Fox, S ; Birch, S ; Tilley, W ; Butler, LM ; Knudsen, K ; Comstock, C ; Rasiah, K ; Grogan, J ; Mahon, KL ; Bianco-Miotto, T ; Ricciardelli, C ; Bohm, M ; Henshall, S ; Delprado, W ; Stricker, P ; Horvath, LG ; Kench, JG (WILEY, 2019-03-01)
  • Item
    Thumbnail Image
    Targeting Mdmx to treat breast cancers with wild-type p53
    Haupt, S ; Buckley, D ; Pang, J-MB ; Panimaya, J ; Paul, PJ ; Gamell, C ; Takano, EA ; Lee, YY ; Hiddingh, S ; Rogers, T-M ; Teunisse, AFAS ; Herold, MJ ; Marine, J-C ; Fox, SB ; Jochemsen, A ; Haupt, Y (NATURE PUBLISHING GROUP, 2015-07-01)
    The function of the tumor suppressor p53 is universally compromised in cancers. It is the most frequently mutated gene in human cancers (reviewed). In cases where p53 is not mutated, alternative regulatory pathways inactivate its tumor suppressive functions. This is primarily achieved through elevation in the expression of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed). In breast cancer (BrCa), the frequency of p53 mutations varies markedly between the different subtypes, with basal-like BrCas bearing a high frequency of p53 mutations, whereas luminal BrCas generally express wild-type (wt) p53. Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial cells and its expression is further elevated in most luminal BrCas, whereas p53 expression is generally low, consistent with wt p53 status. Inducible knockdown (KD) of Mdmx in luminal BrCa MCF-7 cells impedes the growth of these cells in culture, in a p53-dependent manner. Importantly, KD of Mdmx in orthotopic xenograft transplants resulted in growth inhibition associated with prolonged survival, both in a preventative model and also in a treatment model. Growth impediment in response to Mdmx KD was associated with cellular senescence. The growth inhibitory capacity of Mdmx KD was recapitulated in an additional luminal BrCa cell line MPE600, which expresses wt p53. Further, the growth inhibitory capacity of Mdmx KD was also demonstrated in the wt p53 basal-like cell line SKBR7 line. These results identify Mdmx growth dependency in wt p53 expressing BrCas, across a range of subtypes. Based on our findings, we propose that Mdmx targeting is an attractive strategy for treating BrCas harboring wt p53.
  • Item
    Thumbnail Image
    E6AP promotes prostate cancer by reducing p27 expression
    Raghu, D ; Paul, PJ ; Gulati, T ; Deb, S ; Khoo, C ; Russo, A ; Gallo, E ; Blandino, G ; Chan, A-L ; Takano, E ; Sandhu, SK ; Fox, SB ; Williams, S ; Haupt, S ; Gamell, C ; Haupt, Y (IMPACT JOURNALS LLC, 2017-06-27)
    Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins. Accordingly, E3 ligase inhibitors define a rational therapy to restore tumor suppression. The relevant tumor suppressors targeted by E6AP in PC are yet to be fully identified. In this study we show that p27, a key cell cycle regulator, is a target of E6AP in PC. Down regulation of E6AP increases p27 expression and enhances its nuclear accumulation in PC. We demonstrate that E6AP regulates p27 expression by inhibiting its transcription in an E2F1-dependent manner. Concomitant knockdown of E6AP and p27 partially restores PC cell growth, supporting the contribution of p27 to the overall effect of E6AP on prostate tumorigenesis. Overall, we unravelled the E6AP-p27 axis as a new promoter of PC, exposing an attractive target for therapy through the restoration of tumor suppression.
  • Item
    Thumbnail Image
    E6AP Promotes a Metastatic Phenotype in Prostate Cancer
    Gamell, C ; Bandilovska, I ; Gulati, T ; Kogan, A ; Lim, SC ; Kovacevic, Z ; Takano, EA ; Timpone, C ; Agupitan, AD ; Litchfield, C ; Blandino, G ; Horvath, LG ; Fox, SB ; Williams, SG ; Russo, A ; Gallo, E ; Paul, PJ ; Mitchell, C ; Sandhu, S ; Keam, SP ; Haupt, S ; Richardson, DR ; Haupt, Y (CELL PRESS, 2019-12-20)
    Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.
  • Item
    No Preview Available
    Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP
    Paul, PJ ; Raghu, D ; Chan, A-L ; Gulati, T ; Lambeth, L ; Takano, E ; Herold, MJ ; Hagekyriakou, J ; Vessella, RL ; Fedele, C ; Shackleton, M ; Williams, ED ; Fox, S ; Williams, S ; Haupt, S ; Gamell, C ; Haupt, Y (NATURE PUBLISHING GROUP, 2016-12-01)
    Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.
  • Item
    No Preview Available
    Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner
    Haupt, S ; Mitchell, C ; Corneille, V ; Shortt, J ; Fox, S ; Pandolfi, PP ; Castillo-Martin, M ; Bonal, DM ; Cordon-Cardo, C ; Lozano, G ; Haupt, Y (TAYLOR & FRANCIS INC, 2013-06-01)
    UNLABELLED: p53 mutations and downregulation of promyelocytic leukemia (PML) are common genetic alterations in human cancers. In healthy cells these two key tumor suppressors exist in a positive regulatory loop, promoting cell death and cellular senescence. However, the influence of their interplay on tumorigenesis has not been explored directly in vivo. The contribution of PML to mutant p53 driven cancer was evaluated in a mouse model harboring a p53 mutation (p53 (wild-type/R172H) ) that recapitulates a frequent p53 mutation (p53 (R175H) ) in human sporadic and Li-Fraumeni cancers. These mice with PML displayed perturbation of the hematopoietic compartment, manifested either as lymphoma or extramedullary hematopoiesis (EMH). EMH was associated with peripheral blood leucocytosis and macrocytic anemia, suggestive of myeloproliferative- myelodysplastic overlap. In contrast, a complete loss of PML from these mice resulted in a marked alteration in tumor profile. While the incidence of lymphomas was unaltered, EMH was not detected and the majority of mice succumbed to sarcomas. Further, males lacking PML exhibited a high incidence of soft tissue sarcomas and reduced survival, while females largely developed osteosarcomas, without impact on survival. Together, these findings demonstrate that PML is an important tumor suppressor dictating disease development in a pertinent mouse model of human cancer.   KEY POINTS: (1) A mutant p53 allele disrupts hematopoiesis in mice, by promoting lymphomas and myeloproliferative / myelodysplastic overlap. (2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC).
  • Item
    No Preview Available
    E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis
    Wolyniec, K ; Shortt, J ; de Stanchina, E ; Levav-Cohen, Y ; Alsheich-Bartok, O ; Louria-Hayon, I ; Corneille, V ; Kumar, B ; Woods, SJ ; Opat, S ; Johnstone, RW ; Scott, CL ; Segal, D ; Pandolfi, PP ; Fox, S ; Strasser, A ; Jiang, Y-H ; Lowe, SW ; Haupt, S ; Haupt, Y (AMER SOC HEMATOLOGY, 2012-07-26)
    Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in ∼ 60% of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma.