Triple-negative breast cancer (TNBC) constitutes 10 to 15% of all breast cancer and is associated with worse prognosis than other subtypes of breast cancer. Current therapies are limited to cytotoxic chemotherapy, radiation, and surgery, leaving a need for targeted therapeutics to improve outcomes for TNBC patients. Mammalian orthoreovirus (reovirus) is a nonenveloped, segmented, double-stranded RNA virus in the family. Reovirus preferentially kills transformed cells and is in clinical trials to assess its efficacy against several types of cancer. We previously engineered a reassortant reovirus, r2Reovirus, that infects TNBC cells more efficiently and induces cell death with faster kinetics than parental reoviruses. In this study, we sought to understand the mechanisms by which r2Reovirus induces cell death in TNBC cells. We show that r2Reovirus infection of TNBC cells of a mesenchymal stem-like (MSL) lineage downregulates the mitogen-activated protein kinase/extracellular signal-related kinase pathway and induces nonconventional cell death that is caspase-dependent but caspase 3-independent. Infection of different MSL lineage TNBC cells with r2Reovirus results in caspase 3-dependent cell death. We map the enhanced oncolytic properties of r2Reovirus in TNBC to epistatic interactions between the type 3 Dearing M2 gene segment and type 1 Lang genes. These findings suggest that the genetic composition of the host cell impacts the mechanism of reovirus-induced cell death in TNBC. Together, our data show that understanding host and virus determinants of cell death can identify novel properties and interactions between host and viral gene products that can be exploited for the development of improved viral oncolytics. TNBC is unresponsive to hormone therapies, leaving patients afflicted with this disease with limited treatment options. We previously engineered an oncolytic reovirus (r2Reovirus) with enhanced infective and cytotoxic properties in TNBC cells. However, how r2Reovirus promotes TNBC cell death is not known. In this study, we show that reassortant r2Reovirus can promote nonconventional caspase-dependent but caspase 3-independent cell death and that the mechanism of cell death depends on the genetic composition of the host cell. We also map the enhanced oncolytic properties of r2Reovirus in TNBC to interactions between a type 3 M2 gene segment and type 1 genes. Our data show that understanding the interplay between the host cell environment and the genetic composition of oncolytic viruses is crucial for the development of efficacious viral oncolytics.
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http://dx.doi.org/10.1128/JVI.01613-20 | DOI Listing |
BMC Cancer
December 2024
Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Min-De Road, Nanchang, Jiangxi, 330006, China.
Background: Infections are common complications and causes of death during immunochemotherapy in diffuse large B-cell lymphoma (DLBCL). The gut microbiota plays a significant role in bacterial infection, but its relationship and predictive capacity with infectious complications in DLBCL are unknown.
Methods: We performed 16S rRNA gene sequencing of fecal samples collected from 41 patients with newly diagnosed DLBCL at baseline, after every two cycles of standard immunochemotherapy, during infection, and after infection recovery.
Histochem Cell Biol
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Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi, China.
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December 2024
Dr B R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
Cancer, a leading cause of death worldwide, is projected to increase by 76.6% in new cases and 89.7% in mortality by 2050 (WHO 2022).
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December 2024
Division of Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.
Disulfidptosis is a recently identified form of cell death characterized by the aberrant accumulation of cellular disulfides. This process primarily occurs in glucose-starved cells expressing higher levels of SLC7A11 and has been proposed as a therapeutic strategy for cancers with hyperactive SCL7A11. However, the potential for inducing disulfidptosis through other mechanisms in cancers remains unclear.
View Article and Find Full Text PDFCell Death Differ
December 2024
State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China.
Autophagosomes are formed by the enlargement and sealing of phagophores. This is accompanied by the recruitment and release of autophagy-related (Atg) proteins that function therein. Presently, the relationship among factors that act after the initial emergence of the phagophore is unclear.
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