Biology subjects

Sood, A. K.

Publications and source records attributed to Sood, A. K..

7 recordsLinked to original sources

bioRxiv2025

FOLR1-targeted Actinium-225-based Alpha-particle Therapy Eliminates Ovarian Cancer

Despite the advancement in therapies, ovarian cancer treatment is challenging due to poor prognosis and high relapse associated with acquired resistance. Targeting overexpression of FOLR1 in ovarian cancers has proven to be an attractive strategy. The recent FDA approval of FOLR1 targeted antibody drug conjugate has shown promising results albeit resistance with repeated use appears inevitable. Emerging targeted alpha-particle therapies, particularly Actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. The success of alpha-particle therapy relies on tumor specific delivery of the alpha emitters. Herein we describe the first example of FOLR1-targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal PET imaging demonstrated high tumor-specific uptake of FOLR1 in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy achieving marked tumor regression, 80% survival and 40% complete response. The therapy resulted in tumor specific double stranded DNA damage, and no obvious toxicity was observed in normal tissues. Estimated human dosimetry showed high absorbed dose for tumor and minimal absorbed dose for healthy tissues establishing its safety. In totality, FOLR1-targeted 225Ac alpha-particle therapy is an efficacious and safe treatment with high feasibility for clinical translation to fight against ovarian cancer.

bioengineering↗

bioRxiv2025

Copper Sulfide Nanoparticle-Mediated Photothermolysis Induces Immunogenic Cell Death in Ovarian Cancer Cells

Immunotherapy has only limited efficacy against ovarian cancer because of dysfunctional T cells in an immunosuppressive tumor microenvironment. Selective photothermolysis is a technique in which short pulsed laser is used to ablate tissue in targeted regions in a precise spatiotemporally controlled manner. This technique allows targeted tissue ablation without damage to surrounding tissue. In the current study, we demonstrated that ovarian cancer cells treated with photothermolysis mediated by near-infrared-absorbing CuS nanoparticles and 15-ns laser pulses were ingested by human monocyte-derived dendritic cells (MoDCs) more efficiently than were ovarian cancer cells treated with ionizing radiation. Moreover, ingestion of ovarian cancer cells treated with CuS NP-mediated photothermolysis promoted MoDC activation. Immature MoDCs that had been exposed to photothermolysis-treated cancer cells caused greater clonal expansion of co-cultured human CD4+ and CD8+ T cells than did immature MoDCs that had been exposed to ionizing radiation-treated tumor cells. These data indicate that photothermolysis may be used to selectively target and destroy tumor cells and cause them to release antigens and danger signals, which can be recognized by DCs to activate T cells.

immunology↗

bioRxiv2024

Pan-cancer subclonal mutation analysis of 7,827 tumors predicts clinical outcome

Intra-tumor heterogeneity is characterized by a diverse population of tumor clones and subclones which are important drivers of tumor evolution and therapeutic response. However, accurate subclonal reconstruction at scale remains challenging. We developed a machine learning tool, CliPP, and surveyed 9,972 tumors from 32 cancer types. We found that high subclonal mutation load (sML), the fraction of subclonal single nucleotide variants (SNVs) to all SNVs in the coding region, was prognostic of survival (progression free survival or overall survival) in 18 cancer types. In 14 cancers with low to moderate tumor mutation burden (TMB), high sML was associated with better prognosis. In immunotherapy trials for 42 metastatic prostate cancer (mCRPC), high sML was predictive of favorable response to ipilimumab and associated with increased CD8+ T-cell infiltration and decreased macrophage population. A validation using 613 whole-genomes of esophageal adenocarcinoma confirms the favorable effect of high sML and the observed tumor-associated macrophage. Our study identifies sML as a key feature of cancer, suggesting a biphasic relationship between evolutionary dynamics and differential immune environments. Finally, sML may serve as an orthogonal approach to identify likely responders of immune checkpoint blockade in low to moderate TMB tumors.

genomics↗

bioRxiv2024

Deep Quantitative Proteomics Identifies Conserved Proteome Alterations in Low and High-Grade Serous Ovarian Cancers

BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a rare and largely chemoresistant subtype of epithelial ovarian cancer. Unlike treatment for high-grade serous ovarian cancer (HGSOC), management options for LGSOC patients are limited, in part, due to a lack of deep molecular characterization of this disease. To address this limitation, we aimed to define highly conserved proteome alterations in LGSOC by performing deep quantitative proteomic analysis of tumors collected from LGSOC (n=12) and HGSOC (n=24) patients or normal fallopian tube tissues (n=12) and validating proteins within two independent proteomic datasets of LGSOC (n=25) and HGSOC (n=49) tumors. ResultsOur efforts identified 275 protein alterations conserved between LGSOC and HGSOC tumors that exhibit high quantitative correlation between discovery and validation cohorts (Spearman Rho [≥] 0.82, P < 1E-4). Conserved proteins elevated in LGSOC tumors were enriched for pathways regulating cell adhesion and defective cellular apoptosis signaling and candidates mapping as putative drug targets included 5-nucleotidase/ cluster of differentiation 73 (NT5E/CD73). We also identified MUC16 (CA125) as significantly elevated in LGSOC versus HGSOC tumors and confirmed this by immunohistochemistry analysis between three independent reviewers. We also find that MUC16 exhibits a more apical versus membrane-staining pattern in LGSOC tumors, suggesting unique regulation of MUC16 in this disease subtype. ConclusionOur efforts define highly conserved protein alterations distinguishing LGSOC from HGSOC tumors, including CD73, as well as the novel identification that MUC16 is elevated and exhibits more apical staining pattern in LGSOC tumor tissues. These findings deepen our molecular understanding of LGSOC and provide unique insights into highly conserved proteome alterations in LGSOC tumors.

cancer biology↗

bioRxiv2022

Plasma and ovarian metabolomics responses to chronic stress in female mice

BackgroundChronic stress may affect metabolism of amino acids, lipids, and other small molecule metabolites, but these alterations may differ depending on tissue evaluated. We examined metabolomic changes in plasma and ovarian tissue samples from female mice due to chronic stress exposure. MethodsAt 12 weeks old, healthy, female, C57 black mice were randomly assigned to three weeks of chronic stress using daily restraint (2 hours/day; n=9) or normal care (n=10). Metabolomic profiling was conducted on plasma and ovarian tissues. Using the Wilcoxon Rank Test, Metabolite Set Enrichment Analysis, and Differential Network Analysis we identified metabolomic alterations occurring in response to restraint stress. All p-values were corrected for multiple testing using the false discovery rate approach. ResultsIn plasma, individual lysophosphatidylcholines (positively) and the metabolite classes carnitines (positively), diacylglycerols and triacylglycerols (inversely) were associated with restraint stress (adjusted-ps<0.2). In contrast, diacylglycerols and triacylglycerols were increased while carnitines were decreased in ovarian tissue from stressed mice (adjusted-ps<0.2). However, several metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were consistently inversely associated with restraint stress in plasma and ovarian tissue (adjusted-ps<0.2). ConclusionWe identified differences in multiple lipid and amino acid metabolites in plasma and ovarian tissue of female mice after exposure to chronic stress. Some affected metabolites (primarily triacylglycerols and diacylglycerols) exhibited opposite associations with chronic stress in plasma (a marker of systemic influences) versus in ovarian tissue (representing local changes), suggesting research to understand the biological impact of chronic stress needs to consider both systemic and tissue-specific alterations.

animal behavior and cognition↗

bioRxiv2021

Ovarian Tumor Mitochondria Exhibit Abnormal Phenotypes and Blunted Associations with Biobehavioral Factors

Tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and tumor mitochondria remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign and cancerous ovarian tissue in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n=1,435) showed that gene expression of specific mitochondrial proteins in ovarian tumors is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in 51 benign and 128 high-grade epithelial ovarian tumors revealed that compared to benign tissue, tumors exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P<0.001) but similar mitochondrial DNA levels (-3.1%), documenting abnormal mitochondrial phenotypes in tumors. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r=-0.43 to 0.47). In contrast, serous tumors showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in ovarian tumors and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

cancer biology↗

bioRxiv2019

Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in a High-Grade Serous Ovarian Tumor Specimen

Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten primary high-grade serous ovarian tumors and analyzed using proteomics (mass spectrometry and reverse phase protein microarray) and RNA-sequencing analyses. Comparative analyses of transcript and protein abundances revealed independent clustering of enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering between purified collections, driven by overall tumor purity. Comparison of historic prognostic molecular subtypes for HGSOC revealed protein and transcript expression from tumor epithelium correlated most strongly with the differentiated molecular subtype, whereas stromal proteins and transcripts most strongly correlated with mesenchymal subtype. Protein and transcript abundance in tumor epithelium and stromal collections from neighboring sections exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial protein and transcript expression heterogeneity within the tumor microenvironment that directly bears on prognostic signatures and underscore the need to enrich cellular subpopulations for expression profiling.

cancer biology↗