Tubo-ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy and frequently responds to platinum-based chemotherapy because of common genetic and somatic impairment of DNA damage repair (DDR) pathways. The mechanisms of clinical platinum resistance are diverse and poorly molecularly defined. Consequently, there are no biomarkers or medicines that improve patient outcomes. Herein we use single cell mass cytometry (CyTOF) to systematically evaluate the phosphorylation and abundance of proteins known to participate in the DNA damage response (DDR). Single cell analyses of highly characterized HGSC cell lines that phenocopy human patients show that cells with comparable levels of intranuclear platinum, a proxy for carboplatin uptake, undergo different cell fates. Unsupervised analyses revealed a continuum of DDR responses. Decompositional methods were used to identify eight distinct protein modules of carboplatin resistance and sensitivity at single cell resolution. CyTOF profiling of primary and secondary platinum-resistance patient models shows that a complex DDR sensitivity module is strongly associated with response, suggesting it as a potential tool to clinically characterize complex drug resistance phenotypes.
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http://dx.doi.org/10.1101/2024.11.21.624591 | DOI Listing |
Elife
December 2024
Howard Hughes Medical Institute, Stanford University, Stanford, United States.
Defining the cellular factors that drive growth rate and proteome composition is essential for understanding and manipulating cellular systems. In bacteria, ribosome concentration is known to be a constraining factor of cell growth rate, while gene concentration is usually assumed not to be limiting. Here, using single-molecule tracking, quantitative single-cell microscopy, and modeling, we show that genome dilution in cells arrested for DNA replication limits total RNA polymerase activity within physiological cell sizes across tested nutrient conditions.
View Article and Find Full Text PDFCell Oncol (Dordr)
December 2024
Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Purpose: Renal cell carcinoma (RCC), exhibiting remarkable heterogeneity, can be highly infiltrated by regulatory T cells (Tregs). However, the relationship between Treg and the heterogeneity of RCC remains to be explored.
Methods: We acquired single-cell RNA-seq profiles and 537 bulk RNA-seq profiles of TCGA-KIRC cohort.
Discov Oncol
December 2024
Department of Neurosurgery, West China Hospital of Sichuan University, No. 37, Guoxue Lane, Wuhou District, Chengdu, China.
Background: Gliomas, particularly glioblastoma (GBM), are the most common and aggressive primary brain tumors in adults, characterized by high malignancy and frequent recurrence. Despite standard treatments, including surgery, radiotherapy, and chemotherapy, the prognosis for GBM remains poor, with a median survival of less than 15 months and a five-year survival rate below 10%. Tumor heterogeneity and resistance to treatment create significant challenges in controlling glioma progression.
View Article and Find Full Text PDFDiscov Oncol
December 2024
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Background: Low-grade glioma (LGG) is a slow-growing but invasive tumor that affects brain function. Histone deacetylases (HDACs) play a critical role in gene regulation and tumor progression. This study aims to develop a prognostic model based on HDAC-related genes to aid in risk stratification and predict therapeutic responses.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
December 2024
South China University of Technology, School of Chemistry and Chemical Engineering, Wushan St., 510640, Guangzhou, CHINA.
The proceeding of electrochemical CO2 reduction reaction (CO2RR) requires the formation of active hydrogen species for CO2 protonation, while traditional catalysts fail to balance the rate of hydrogen supply and CO2 protonation. Herein, we propose a "hydrogen on demand" mechanism, in which the polarity of the adsorbed CO2 is enhanced to allow the capture of hydrogen from water without forming free hydrogen species, realizing the matching rate of hydrogen supply and CO2 protonation. As a proof of concept, we construct Zn-N sites modified by Se atoms, allowing the proceeding of CO2RR under the "hydrogen on demand" mechanism with superior efficiency.
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