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3 results on '"Niko Thio"'

1. Caspase-2 protects against ferroptotic cell death

Author

Swati Dawar, Mariana C. Benitez, Yoon Lim, Toby A. Dite, Jumana M. Yousef, Niko Thio, Sylvain Garciaz, Thomas D. Jackson, Julia V. Milne, Laura F. Dagley, Wayne A. Phillips, Sharad Kumar, and Nicholas J. Clemons

Subjects
Cytology, QH573-671
Abstract

Abstract Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to the downregulation of stress response genes including SESN2, HMOX1, SLC7A11, and sensitizes mutant-p53 cancer cells to cell death induced by various ferroptosis-inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone-mediated autophagic degradation of GPX4 to promote the survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant p53. Our results provide evidence for a novel function of caspase-2 in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.

Published
2024
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2. The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

Author

Andrew R. Green, David L Goode, Simone M Rowley, Jia-Min Pang, Kylie L. Gorringe, Ian G. Campbell, Tanjina Kader, Dane Cheasley, Emad A. Rakha, Prue Hill, G. Bruce Mann, Kenneth Elder, Niko Thio, Stephen B. Fox, David J Byrne, Timothy Semple, Islam M. Miligy, and Magnus Zethoven

Subjects
0301 basic medicine, Copy number analysis, Malignancy, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Atypia, Carcinoma, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, skin and connective tissue diseases, Cancer genetics, neoplasms, business.industry, Cancer, Ductal carcinoma, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Breast carcinoma, business
Abstract

Intraductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had coexisting ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activating PIK3CA mutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/or IDC, only one of which had papillary histology. In contrast to pure IDP, PIK3CA mutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence of PIK3CA mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.

Published
2020

3. The molecular origin and taxonomy of mucinous ovarian carcinoma

Author

Georgia Chenevix-Trench, Jan Pyman, David G. Hunstman, Hugo Saunders, Linda Mileshkin, Dane Cheasley, Alison Maree Hadley, Nadia Traficante, Clare L. Scott, Diane Provencher, Niko Thio, Clare G Fedele, Joy Hendley, Jason Li, Michael S. Anglesio, Prue E. Allan, Siobhan Hughes, Magnus Zethoven, Timothy Semple, Tom Jobling, Martin Köbel, Michael Christie, Goli Samimi, Kylie L. Gorringe, Anne Marie Mes-Masson, George Au-Yeung, Yoland Antill, Andrew N. Stephens, Cécile Le Page, Carolina Salazar, Kathryn Alsop, Anna deFazio, Kurosh Rahimi, Richard Lupat, Orla McNally, Georgina L Ryland, Jessica N. McAlpine, Ian G. Campbell, Renee Demeo, Rhiannon Dudley, Simone M Rowley, Michael Churchman, C. Blake Gilks, Gwo-Yaw Ho, Stephen B. Fox, Yoke Eng Chiew, Sally M Hunter, David D.L. Bowtell, Charlie Gourley, Catherine J. Kennedy, Zhongyue Xing, Scott H. Kaufmann, Nicole Fairweather, Kimberly R. Kalli, Alison Brand, Ragwha Sharma, Maret Böhm, Sian Fereday, Matthew Wakefield, Michelle C. Torres, Alice J. Sharpe, Neville F. Hacker, Sumitra Ananda, and Kaushalya C. Amarasinghe

Subjects
0301 basic medicine, Science, General Physics and Astronomy, 02 engineering and technology, Disease, Carcinoma, Ovarian Epithelial, Article, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, 03 medical and health sciences, Ovarian cancer, Ovarian carcinoma, Cancer genomics, medicine, Carcinoma, Humans, lcsh:Science, Survival analysis, Ovarian Neoplasms, Multidisciplinary, business.industry, Gene Expression Profiling, Sequence Analysis, DNA, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Adenocarcinoma, Mucinous, Survival Analysis, 3. Good health, Gene Expression Regulation, Neoplastic, Gene expression profiling, 030104 developmental biology, Mutation, Etiology, Cancer research, Adenocarcinoma, Female, lcsh:Q, 0210 nano-technology, business
Abstract

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases., Whether mucinous ovarian carcinoma (MOC) arises from cells at the ovary or from metastases from other primary sites is an unanswered question. Here, Cheasley et al perform a genetic analysis of the disease, showing that MOC arises at the ovary.

Published
2019

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