Article
Oncology
Hassina Massudi, Jie-Si Luo, Jessica K. Holien, Satyanarayana Gadde, Sukriti Krishan, Mika Herath, Jessica Koach, Brendan W. Stevenson, Michael A. Gorman, Pooja Venkat, Chelsea Mayoh, Xue-Qun Luo, Michael W. Parker, Belamy B. Cheung, Glenn M. Marshall
Summary: Neuroblastoma, the most common solid tumor in early childhood, has a poor survival rate among children with advanced disease. This study identified a protein called PA2G4 as a cofactor for the MYCN oncogene and developed a compound called WS6 and its analogues to inhibit PA2G4 and MYCN protein levels and reduce tumor cell growth. The novel WS6 analogues showed promise as inhibitors of MYCN and PA2G4 oncogenic functions and may have implications for other MYCN-driven cancers.
Article
Multidisciplinary Sciences
Zsuzsanna Nagy, Janith A. Seneviratne, Maxwell Kanikevich, William Chang, Chelsea Mayoh, Pooja Venkat, Yanhua Du, Cizhong Jiang, Alice Salib, Jessica Koach, Daniel R. Carter, Rituparna Mittra, Tao Liu, Michael W. Parker, Belamy B. Cheung, Glenn M. Marshall
Summary: The gain of 17q21-ter in neuroblastoma leads to overexpression of ALYREF, which forms a complex with MYCN and regulates MYCN stability via the deubiquitinating enzyme, USP3.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Xiaosong Hu, Ruochen Liu, Jianbing Hou, Wen Peng, Sicheng Wan, Minghao Xu, Yongsen Li, Guanghui Zhang, Xuan Zhai, Ping Liang, Hongjuan Cui
Summary: This study reveals the critical oncogenic role of SMARCE1 gene in neuroblastoma, particularly in cases with MYCN amplification. SMARCE1 interacts with MYCN to mediate transcriptional activation of downstream target genes, promoting neuroblastoma proliferation and tumorigenicity. These findings provide a new potential therapeutic target for neuroblastoma with 17q21-ter gain and MYCN amplification.
Article
Medicine, Research & Experimental
Cui Shi, Kunhui Huang, John Soto, Renuka Sankaran, Vrinda Kalia, Onyekwere Onwumere, Michael Young, Linda Einbond, Stephen Redenti
Summary: Piperlongumine (PL) has significant anti-proliferation and cell-death effects on metastatic retinoblastoma cells, and it also reduces the level of MYCN oncogene and incorporates into extracellular vesicles for systemic anti-cancer effects on target cells.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Cell Biology
Eunice Cho, Hua Jane Lou, Leena Kuruvilla, David A. Calderwood, Benjamin E. Turk
Summary: This study identifies PPP6C as a crucial phosphatase for MEK in the ERK pathway, which is frequently mutated or downregulated in melanoma. Loss of PPP6C leads to hyperphosphorylation of MEK, enhancing signaling through the pathway and reducing sensitivity to MEK inhibitors. Its recurrent mutations in melanoma cause MEK hyperphosphorylation, suggesting their role in promoting the disease by activating the core oncogenic pathway.
Article
Biology
Gary K. L. Chan, Samantha Maisel, Yeonjoo C. Hwang, Bryan C. Pascual, Rebecca R. B. Wolber, Phuong Vu, Krushna C. Patra, Mehdi Bouhaddou, Heidi L. Kenerson, Huat C. Lim, Donald Long, Raymond S. Yeung, Praveen Sethupathy, Danielle L. Swaney, Nevan J. Krogan, Rigney E. Turnham, Kimberly J. Riehle, John D. Scott, Nabeel Bardeesy, John D. Gordan
Summary: Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. The downstream oncogenic signaling mechanisms of PKA activation in human cancer were explored using phosphoproteomics and kinase activity profiling. Two signaling networks, RAS/MAPK components and an AURKA/GSK3 sub-network, were identified, both affecting MYC oncoproteins. Primary mechanism of PKA effects on MYC was found to be translation, which could be blocked with the eIF4A inhibitor zotatifin, suggesting a potential treatment strategy for PKA-driven cancers.
Article
Medicine, Research & Experimental
Argelia Calvillo-Robledo, Rodolfo Daniel Cervantes-Villagrana, Paula Morales, Bruno A. Marichal-Cancino
Summary: GPR55 is an orphan receptor that has been found to play a crucial role in various pathophysiological processes. This receptor can be modulated by cannabinoids and is proposed to be a part of the endocannabinoid system. The LPI/GPR55 axis is involved in cell survival and tumor progression, and has potential as a biomarker for cancer diagnosis.
Article
Biochemistry & Molecular Biology
Marine Beck, Mathilde Baranger, Ahlam Moufok-Sadoun, Emilie Bersuder, Isabelle Hinkel, Georg Mellitzer, Elisabeth Martin, Laetitia Marisa, Isabelle Duluc, Aurelien de Reynies, Christian Gaiddon, Jean-Noel Freund, Isabelle Gross
Summary: This study focused on the atypical cadherin MUCDHL, which is down-regulated in colorectal tumors, especially in tumors with worse prognosis. Loss of MUCDHL enhanced tumor incidence and burden in intestinal tumor-prone mice, and targeted key oncogenic signaling pathways through its extracellular domain. The study illustrates how the loss of a gene critical for the morphological and functional features of mature cells contributes to tumorigenesis by dysregulating oncogenic pathways.
Review
Biochemistry & Molecular Biology
Dejun Liu, Xinqiang Wan, Xiangxiang Shan, Rengen Fan, Wenzhang Zha
Summary: miRNAs, previously considered undruggable, have recently been shown to be targetable with small molecules such as SMIs and SMDs, which inhibit their biogenesis or induce degradation. These small molecules demonstrate high potency and specificity in miRNA inhibition, providing new opportunities for therapeutic development towards previously considered undruggable targets.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Soraya Learte-Aymami, Pau Martin-Malpartida, Lorena Roldan-Martin, Giuseppe Sciortino, Jose R. Couceiro, Jean-Didier Marechal, Maria J. Macias, Jose L. Mascarenas, M. Eugenio Vazquez
Summary: A short peptide was designed to reversibly bind to KRAS upon coordination to Pd(II), inhibiting its activated pathways in live cells. The peptide can efficiently internalize into cells and inhibit the MAPK kinase cascade.
COMMUNICATIONS CHEMISTRY
(2022)
Article
Biotechnology & Applied Microbiology
Divya Thomas, Satish Sagar, Xiang Liu, Hye-Rim Lee, James A. Grunkemeyer, Paul M. Grandgenett, Thomas Caffrey, Kelly A. O'Connell, Benjamin Swanson, Lara Marcos-Silva, Catharina Steentoft, Hans H. Wandall, Hans Carlo Maurer, Xianlu Laura Peng, Jen Jen Yeh, Fang Qiu, Fang Yu, Ragupathy Madiyalakan, Kenneth P. Olive, Ulla Mandel, Henrik Clausen, Michael A. Hollingsworth, Prakash Radhakrishnan
Summary: Aberrant expression of MUC16 is associated with PDAC progression, tumor subtypes, metastasis and patient survival. MUC16 enhances tumor malignancy through ErB receptor-mediated oncogenic signaling pathways. Treatment with mAb AR9.6 reduces metastasis and tumor growth in PDAC-bearing mice.
Article
Biochemistry & Molecular Biology
Eugene Choi, Sung Jean Park, Gunhee Lee, Seung Kew Yoon, Minho Lee, Suk Kyeong Lee
Summary: The GNAQ T96S hotspot mutation is a common mutation in HCC patients, potentially playing an oncogenic role by enhancing the GNAQ signaling pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Antonia Schubert, Michael Boutros
Summary: Extracellular vesicles (EVs) have emerged as potential diagnostic and prognostic markers for cancer therapy, yet much remains unknown about their exact mechanisms of signaling specificity and cargo transfer. Several signaling cascades utilize EVs for signaling in tumor-stroma interaction, including key pathways such as Wnt and TGF-beta, which are tightly associated with tumor progression and metastasis. Multiple mechanisms of how EVs interplay with signaling cascades to mediate complex processes have been described, shedding light on the potential therapeutic applications and gaps in knowledge.
MOLECULAR ONCOLOGY
(2021)
Article
Multidisciplinary Sciences
Alexandra D'Oto, Jie Fang, Hongjian Jin, Beisi Xu, Shivendra Singh, Anoushka Mullasseril, Victoria Jones, Ahmed Abu-Zaid, Xinyu von Buttlar, Bailey Cooke, Dongli Hu, Jason Shohet, Andrew J. Murphy, Andrew M. Davidoff, Jun Yang
Summary: The histone demethylase KDM6B is essential for neuroblastoma cell survival and promotes an oncogenic CDK4/6-pRB-E2F pathway through H3K27me3-dependent enhancer-promoter interactions.
NATURE COMMUNICATIONS
(2021)
Article
Gastroenterology & Hepatology
Lu Tian, Luqing Zhao, Karen Man-Fong Sze, Charles Shing Kam, Vanessa Sheung-In Ming, Xia Wang, Vanilla Xin Zhang, Daniel Wai-Hung Ho, Tan-To Cheung, Lo-Kong Chan, Irene Oi-Lin Ng
Summary: RalA is significantly up-regulated in HCC patients and associated with aggressive tumor behavior and poor prognosis. Its up-regulation is driven by copy number gain, while RalGAPA2 knockdown increases RalA activity. Tumors with down-regulated RalGAPA2 and up-regulated RalA display more aggressive behavior and poorer survival, with Ral inhibition showing potential as a therapeutic approach.
Article
Medicine, Research & Experimental
Johannes Zeller, Karen S. Cheung Tung Shing, Tracy L. Nero, James D. McFadyen, Guy Krippner, Balazs Bogner, Sheena Kreuzaler, Jurij Kiefer, Verena K. Horner, David Braig, Habiba Danish, Sara Baratchi, Mark Fricke, Xiaowei Wang, Michel G. Kather, Bernd Kammerer, Kevin J. Woollard, Prerna Sharma, Craig J. Morton, Geoffrey Pietersz, Michael W. Parker, Karlheinz Peter, Steffen U. Eisenhardt
Summary: C-reactive protein (CRP) is highly upregulated during inflammatory reactions and exhibits pro-inflammatory effects. We discovered a mechanism in which CRP undergoes conformational changes, resulting in highly inflammatory forms. By designing a low molecular weight CRP inhibitor that mimics phosphocholine, we demonstrated its ability to inhibit CRP-driven inflammation while preserving its pathogen-defense functions. This represents a promising and potentially broad-spectrum anti-inflammatory therapy.
EMBO MOLECULAR MEDICINE
(2023)
Article
Oncology
Janith A. Seneviratne, Daniel R. Carter, Rituparna Mittra, Andrew Gifford, Patrick Y. Kim, Jie-Si Luo, Chelsea Mayoh, Alice Salib, Aldwin S. Rahmanto, Jayne Murray, Ngan C. Cheng, Zsuzsanna Nagy, Qian Wang, Ane Kleynhans, Owen Tan, Selina K. Sutton, Chengyuan Xue, Sylvia A. Chung, Yizhuo Zhang, Chengtao Sun, Li Zhang, Michelle Haber, Murray D. Norris, Jamie I. Fletcher, Tao Liu, Pierre J. Dilda, Philip J. Hogg, Belamy B. Cheung, Glenn M. Marshall
Summary: High expression of mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2) predicts poor prognosis and a more malignant phenotype in neuroblastoma. Inhibiting this transporter reduces cell viability in neuroblastoma cells. The histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) is the most effective drug against mutant TP53 neuroblastoma cells. SAHA and PENAO together delay tumor progression in neuroblastoma mouse models.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Biotechnology & Applied Microbiology
Prahlad V. Raninga, Yaowu He, Keshava K. Datta, Xue Lu, Uma R. Maheshwari, Pooja Venkat, Chelsea Mayoh, Harsha Gowda, Murugan Kalimutho, John D. Hooper, Kum Kum Khanna
Summary: Approximately 50%-55% of HGSOC patients have MYC oncogenic pathway activation. Enrichment of NRF2-controlled genes and increased thioredoxin redox activity were observed in MYC-high HGSOC tumors. Treatment with the TrxR1 inhibitor auranofin resulted in growth inhibition and apoptosis in MYC-high HGSOC cells, and auranofin also significantly reduced tumor growth in a patient-derived tumor xenograft model. Inhibition of glycolysis in MYC-high cells led to a switch to glutamine metabolism for survival. Depletion of glutamine, either through starvation or with auranofin, effectively reduced tumor growth in HGSOC cells and xenograft models, suggesting a potential combination therapy for MYC-high HGSOC patients.
Article
Multidisciplinary Sciences
Mandy L. Ballinger, Swetansu Pattnaik, Piyushkumar A. Mundra, Milita Zaheed, Emma Rath, Peter Priestley, Jonathan Baber, Isabelle Ray-Coquard, Nicholas Isambert, Sylvain Causeret, Winette T. A. van der Graaf, Ajay Puri, Florence Duffaud, Axel Le Cesne, Beatrice Seddon, Coonoor Chandrasekar, Joshua D. Schiffman, Andrew S. Brohl, Paul A. James, Jean-Emmanuel Kurtz, Nicolas Penel, Ola Myklebost, Leonardo A. Meza-Zepeda, Hilda Pickett, Maya Kansara, Nicola Waddell, Olga Kondrashova, John Pearson, Andrew P. Barbour, Shuai Li, Tuong L. Nguyen, Diane Fatkin, Robert M. Graham, Eleni Giannoulatou, Melissa J. Green, Warren Kaplan, Shyamsundar Ravishankar, Joseph Copty, Joseph E. Powell, Edwin Cuppen, Kristel van Eijk, Jan Veldink, Jin-Hee Ahn, Jeong Eun Kim, R. Lor Randall, Kathy Tucker, Ian Judson, Rajiv Sarin, Thomas Ludwig, Emmanuelle Genin, Jean-Francois Deleuze, Michelle Haber, Glenn Marshall, Murray J. Cairns, Jean-Yves Blay, David M. Thomas
Summary: Cancer genetics has focused on epithelial malignancies, but this study explores specific pathways related to sarcomas, rare malignancies derived from embryonic mesoderm. Germline sequencing of sporadic cases and healthy controls reveals two sarcoma-specific pathways involved in mitotic and telomere functions. Centrosome gene variants are linked to specific tumors, while heritable defects in the shelterin complex increase susceptibility to sarcomas, melanomas, and thyroid cancers. These findings highlight the role of heritable defects in mitotic and telomere biology in sarcoma risk.
Article
Multidisciplinary Sciences
Pamela Ajuyah, Chelsea Mayoh, Loretta M. S. Lau, Paulette Barahona, Marie Wong, Hazel Chambers, Fatima Valdes-Mora, Akanksha Senapati, Andrew J. Gifford, Colleen D'Arcy, Jordan R. Hansford, Neevika Manoharan, Wayne Nicholls, Molly M. Williams, Paul J. Wood, Mark J. Cowley, Vanessa Tyrrell, Michelle Haber, Paul G. Ekert, David S. Ziegler, Dong-Anh Khuong-Quang
Summary: This study reports a new subtype of midline gliomas with similar features to DMG but lacking the H3K27M mutation. These tumors have recurrent mutations in ACVR1 or EGFR and high expression of EZHIP. They have a poor prognosis similar to H3K27M DMG and exhibit distinct transcriptome and methylome profiles. The study provides new insights into the mechanism and pathway regulation of these tumors, potentially opening new therapeutic avenues.
SCIENTIFIC REPORTS
(2023)
Article
Genetics & Heredity
Chelsea Mayoh, Andrew J. Gifford, Rachael Terry, Loretta M. S. Lau, Marie Wong, Padmashree Rao, Tyler Shai-Hee, Federica Saletta, Dong-Anh Khuong-Quang, Vicky Qin, Marion K. Mateos, Deborah Meyran, Katherine E. Miller, Aysen Yuksel, Emily V. A. Mould, Rachel Bowen-James, Dinisha Govender, Akanksha Senapati, Nataliya Zhukova, Natacha Omer, Hetal Dholaria, Frank Alvaro, Heather Tapp, Yonatan Diamond, Luciano Dalla Pozza, Andrew S. Moore, Wayne Nicholls, Nicholas G. Gottardo, Geoffrey McCowage, Jordan R. Hansford, Seong-Lin Khaw, Paul J. Wood, Daniel Catchpoole, Catherine E. Cottrell, Elaine R. Mardis, Glenn M. Marshall, Vanessa Tyrrell, Michelle Haber, David S. Ziegler, Orazio Vittorio, Joseph A. Trapani, Mark J. Cowley, Paul J. Neeson, Paul G. Ekert
Summary: By combining immunohistochemistry, RNA sequencing, and whole-genome sequencing, we identified a novel 15-gene immune signature, IPASS, associated with CD8(+) T-cell infiltration in high-risk paediatric cancers. Using this signature, we estimated that up to 31% of high-risk cancers exhibit infiltrating T-cells. Furthermore, we found that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression, and neoantigen load and TMB are not predictive of T-cell infiltration in paediatric cancers.
Article
Multidisciplinary Sciences
Jordan F. Hastings, Sharissa L. Latham, Alvin Kamili, Madeleine S. Wheatley, Jeremy Z. R. Han, Marie Wong-Erasmus, Monica Phimmachanh, Max Nobis, Chiara Pantarelli, Antonia L. Cadell, Yolande E. I. O'Donnell, King Ho Leong, Sophie Lynn, Fan-Suo Geng, Lujing Cui, Sabrina Yan, Joanna Achinger-Kawecka, Clare Stirzaker, Murray D. Norris, Michelle Haber, Toby N. Trahair, Frank Speleman, Katleen De Preter, Mark J. Cowley, Ozren Bogdanovic, Paul Timpson, Thomas R. Cox, Walter Kolch, Jamie I. Fletcher, Dirk Fey, David R. Croucher
Summary: Gene expression noise promotes stochastic drug resistance in rare cancer cells. However, when integrated across multiple components of an apoptotic signaling network, the influence of noise leads to a higher frequency of chemoresistant neuroblastoma cells. These cells are characterized by JNK impairment and retain a memory of their resistant state even after chemotherapy treatment.
Article
Oncology
Hassina Massudi, Jie-Si Luo, Jessica K. Holien, Satyanarayana Gadde, Sukriti Krishan, Mika Herath, Jessica Koach, Brendan W. Stevenson, Michael A. Gorman, Pooja Venkat, Chelsea Mayoh, Xue-Qun Luo, Michael W. Parker, Belamy B. Cheung, Glenn M. Marshall
Summary: Neuroblastoma, the most common solid tumor in early childhood, has a poor survival rate among children with advanced disease. This study identified a protein called PA2G4 as a cofactor for the MYCN oncogene and developed a compound called WS6 and its analogues to inhibit PA2G4 and MYCN protein levels and reduce tumor cell growth. The novel WS6 analogues showed promise as inhibitors of MYCN and PA2G4 oncogenic functions and may have implications for other MYCN-driven cancers.
Article
Chemistry, Multidisciplinary
Catherine G. Fitzgerald Dickmann, Alexander F. F. McDonald, Nhi Huynh, Angela Rigopoulos, Zhanqi Liu, Nancy Guo, Laura D. D. Osellame, Michael A. A. Gorman, Michael W. W. Parker, Hui K. K. Gan, Andrew M. M. Scott, Uwe Ackermann, Ingrid J. G. Burvenich, Jonathan M. M. White
Summary: A novel molecule, [F-18]BiPET-2, radiolabelled with positron emitting fluorine-18, has been developed and evaluated in vitro and preclinically in glioblastoma models.
CHEMICAL COMMUNICATIONS
(2023)