Biology subjects

Thomas, G. V.

Publications and source records attributed to Thomas, G. V..

8 recordsLinked to original sources

bioRxiv2025

Mitochondrial Translation Inhibition Uncovers a Critical Metabolic-Epigenetic Interface in Renal Cell Carcinoma

Background/ObjectivesRenal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy. MethodsWe employed comprehensive metabolomic profiling, subcellular proteomics, and functional assays to characterize the effects of tigecycline on RCC cell lines, patient-derived organoids, and xenograft models. The synergistic potential of tigecycline with the histone deacetylase inhibitor entinostat was evaluated using combination index analysis. ResultsTigecycline selectively inhibited mitochondrial translation in RCC cells, reducing mitochondrially-encoded proteins while sparing nuclear-encoded components, profoundly disrupting mitochondrial bioenergetics and reducing tumor growth in xenograft models. Subcellular proteomic analyses revealed that tigecycline treatment triggered significant accumulation of multiple histone variants concurrent with cell cycle arrest. Based on this discovery, combined treatment with tigecycline and entinostat demonstrated remarkable synergism across RCC cell lines and patient derived organoids. ConclusionsOur findings identify a promising therapeutic opportunity by targeting the crosstalk between mitochondrial function and epigenetic homeostasis in RCC, with potential for rapid clinical translation given the established pharmacological profiles of both agents.

cancer biology↗

bioRxiv2024

Deciphering single-cell heterogeneity and cellular ecosystem dynamics during prostate cancer progression

Prostate cancer (PC) progresses from benign epithelium through pre-malignant lesions, localized tumors, metastatic dissemination, and castration-resistant stages, with some cases exhibiting phenotype plasticity under therapeutic pressure. However, high-resolution insights into how cell phenotypes evolve across successive stages of PC remain limited. Here, we present the Prostate Cancer Cell Atlas (PCCAT) by integrating [~]710,000 single cells from 197 human samples covering a spectrum of tumor stages. This comprehensive analysis dissects the cellular landscape and characterizes key cell types and molecular features that associate with PC progression and prognosis. In malignant cells, we highlight a distinctive profile denoted by high Major Histocompatibility Complex (MHC) expression, low Androgen Receptor (AR) activity, and enhanced stemness programs associated with enzalutamide resistance. Moreover, we reveal several cell states strongly correlated with PC progression and adverse prognosis, including lineage plasticity-like malignant cells (LPCs), neuroendocrine tumor cells, pericytes, and matrix cancer-associated fibroblasts (mCAFs). Furthermore, we uncover shared cell states that underpin the immune suppressive tumor microenvironment in advanced PC, including activated regulatory T cells, exhausted CD8+ T cells, and SPP1-expressing macrophages. Lastly, we pinpoint a spatial niche composed of mCAFs and SPP1-expressing macrophages localized near the tumor boundary in aggressive PC, which correlates with poor prognosis. Overall, our work provides a valuable resource and offers deeper insights into the diverse cell states, dynamics, and functional characteristics involved in PC progression at single-cell resolution.

cancer biology↗

bioRxiv2024

Comparative Transcriptomes of Canine and Human Prostate Cancers Identify Mediators of Castration Resistance

Prostate cancer continues to be one of the most lethal cancers in men. While androgen-deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration-resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrate an androgen indifferent phenotype, characterized by low androgen receptor and neuroendocrine associated genes. Notably, we identified two genes, ISG15 and AZGP1 that were consistently up- and downregulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P, and IFITM1, that exhibited similar expression patterns in both species. Protein-protein interaction network analysis demonstrated that these 5 genes were part of a larger network of interferon-induced genes, suggesting that they may act together in signaling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach.

genetics↗

bioRxiv2024

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFN{gamma} pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFN{gamma} pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

cancer biology↗

bioRxiv2023

Multiplex imaging of localized prostate tumors reveals changes in mast cell type composition and spatial organization of AR-positive cells in the tumor microenvironment

Mapping spatial interactions of cancer, immune and stromal cells present novel opportunities for patient stratification and for advancing immunotherapy. While single-cell studies revealed significant molecular heterogeneity in prostate tumors, there is currently no understanding of how immune cell heterogeneity impacts spatial coordination between tumor and stromal cells in localized tumors. Here, we used cyclic immunofluorescent imaging on whole-tissue sections to uncover novel spatial associations between cancer and stromal cells in low- and high-grade prostate tumors and tumor-adjacent normal tissues. Our results provide a spatial map of 699,461 single-cells that show epigenetic and molecular differences in distinct clinical grades. We report unique populations of mast cells that differentially express CD44, CD90 and Granzyme B (GZMB) and demonstrate GZMB+ mast cells are spatially associated with M2 macrophages in prostate tumors. Finally, we uncover recurrent neighborhoods that are primarily driven by androgen receptor positive (AR+) stromal cells and identify transcriptional networks active in AR+ prostate stroma.

cancer biology↗

bioRxiv2021

Single-cell analysis of localized low- and high-grade prostate cancers

Approximately, 30% of early-stage localized prostate cancer cases reoccur within 5 to 10 years [1, 2]. However, identifying precise molecular subtypes attributable to specific stages of prostate cancer has proven difficult due to high heterogeneity within localized tumors [3-5]. Bulk assays represent a population average, which is a result of the heterogeneity that exists at the individual prostate cancer cell level [6]. Here, we sequenced the accessible chromatin regions of 14,424 single-cells collected from 18 fresh-frozen prostate tumors using sci-ATAC-seq [7, 8]. We observed that shared chromatin features among low-grade prostate cancer epithelial cells were lost in high-grade tumors. Despite this loss, all high-grade tumors exhibited an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites within their accessible chromatin regions, indicating a shared trans-regulatory program. Single-cell analysis of the differentially accessible regions in high- versus low-grade prostate tumors identified two unique genes encoding neuronal adhesion molecules, NRXN1 and NLGN1. We found that NRXN1 and NLGN1 are expressed in the epithelial luminal, basal and neuroendocrine cells, as well as the immune, endothelial and neuronal cell types in all prostate tumors. Overall, these results provide a deeper understanding of the active gene regulatory networks in low- and high-grade prostate tumors at a striking resolution and provide critical insights for molecular stratification of the disease.

cancer biology↗

bioRxiv2020

An Integrated Clinical, Omic, and Image Atlas of an Evolving Metastatic Breast Cancer

Mechanisms of therapeutic resistance manifest in metastatic cancers as tumor cell intrinsic alterations and extrinsic microenvironmental influences that can change during treatment. To support the development of methods for the identification of these mechanisms in individual patients, we present here an Omic and Multidimensional Spatial (OMS) Atlas generated from four serial biopsies of a metastatic breast cancer patient during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata including treatment times and doses, anatomic imaging, and blood-based response measurements to exploratory analytics including comprehensive DNA, RNA, and protein profiles, images of multiplexed immunostaining, and 2- and 3-dimensional scanning electron micrographs. These data reveal aspects of therapy-associated heterogeneity and evolution of the cancers genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples showing how integrative analyses of these data provide insights into potential mechanisms of response and resistance, and suggest novel therapeutic vulnerabilities.

cancer biology↗

bioRxiv2020

Identification of clinical combination therapies to induce durable responses in kidney cancers

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high throughput drug screen to multiple human kidney cancer cells, we identified the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acted synergistically in cells to markedly reduce cell viability. Importantly, the combination was well tolerated and caused tumor regression in vivo. Transcriptional and phosphoproteomic profiling revealed that the combination converged to downregulate the MAPK-ERK signaling pathway, a result not predicted by single agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergized with either dasatinib or cabozantinib to increase its efficacy. This study, by employing approved, clinically relevant drugs provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

cancer biology↗