Biology subjects

Theodorescu, D.

Publications and source records attributed to Theodorescu, D..

4 recordsLinked to original sources

bioRxiv2025

Loss of the Y chromosome drives cancer metabolic reprogramming

Metabolic reprogramming promotes cancer aggressiveness and an immune-suppressive tumor microenvironment. Loss of the Y chromosome (LOY) drives both phenotypes in bladder cancer (BC). We investigated the hypothesis that LOY leads to metabolic reprogramming using untargeted metabolomic profiling of human BC cells and analysis of pan-cancer transcriptomic datasets. This revealed that aerobic glycolysis is activated in LOY BC cells. Since prior work showed that expression of collagen receptor DDR2 drives BC progression and DDR2 is a regulator of tumor metabolism, we investigated if DDR2 is implicated in metabolic reprogramming of LOY-tumors. Analysis of scRNAseq data from 251 patients with 12 tumor types found that LOY and DDR2 expression promote aerobic glycolysis, and this was confirmed by metabolomics. Deletion of DDR2 in LOY BC cells reduced glycolytic flux, inhibited cell proliferation, reduced EMT and stemness features, and promoted apoptosis. Our data provide a rationale for using LOY as a tumor selection biomarker for DDR2 targeted therapeutics. TeaserLoss of the Y chromosome augments glycolytic metabolism in bladder cancer cells, and this is in part dependent on the collagen receptor DDR2.

cancer biology↗

bioRxiv2025

Human iPSC-derived prostate organoids with germline BRCA2 mutation undergo tumorigenic transformations

The lack of physiologically relevant in vitro prostate models has impeded studies of organ development and prostate tumorigenesis. We reprogrammed peripheral blood mononuclear cells (PBMCs) from individuals with and without pathogenic-germline BRCA2 mutation (MUT_BRCA2, CON_BRCA2) into induced pluripotent stem cells (iPSCs), which showed no differences in morphology, proliferation, or pluripotency markers. Differentiation of MUT_BRCA2 iPSCs into prostate organoids (iPROS) using defined growth factors and signaling molecules resulted in disrupted morphology, impaired polarity, increased proliferation, and elevated prostate-specific antigen (PSA) secretion compared to CON_BRCA2 iPROS. Transcriptomic profiling revealed early prostate cancer (PCa) signatures. Upon exposure to dietary carcinogens, MUT_BRCA2 iPROS showed further PSA elevation, enhanced proliferation, AMACR upregulation, p63 reducetion are markers of aggressive PCa. In vivo, MUT_BRCA2 iPROS formed tumors in immunodeficient mice. This patient-derived iPROS-platform recapitulates human-prostate mopphology and function, models early tumorigenesis events, and provides a valuable tool for studying PCa biology and enabling personalized drug discovery. IN BRIEFIn this study, we developed patients iPSC-derived prostate organoids (iPROS) with or without a pathogenic BRCA2 germline mutation that display human-prostate like morphology and function. MUT_BRCA2 iPROS displayed disrupted morphology, early tumorigenic changes, and formed tumors in mice. Upon carcinogen exposure, they showed markers of aggressive prostate cancer. This platform models early prostate tumorigenesis and enables personalized studies of cancer initiation and therapeutic response.

cancer biology↗

bioRxiv2021

The Origin of Bladder Cancer from Mucosal Field Effects

We used whole-organ mapping to study loco-geographic molecular changes in evolution of human bladder cancer from mucosal field effects. The integrative multi-platform analyses based on genome-wide RNA sequencing, methylation, copy number variations, and whole exome sequencing identified over 100 dysregulated canonical pathways involving immunity, tissue differentiation and transformation as initiators of bladder carcinogenesis. Widespread dysregulation of interleukin signaling was the dominant change signifying the important role of inflammation and immunity in the incipient phases of urothelial carcinogenesis. The analyses of mutational patterns identified three types of mutations based on their geographic distribution and variant allele frequencies. The most common were low frequency subclonal mutations restricted to individual mucosal samples which were the progeny of their respective uroprogenitor cells. The two additional types of mutations were associated with clonal expansion and involved large areas of bladder mucosa. The first group referred to as mutations, showed a low mutational frequency across the mucosa. The second group referred to as {beta} mutations increased in their frequencies with disease progression and a large proportion of them represented mutated transcriptional regulators controlling proliferation. Time modeling revealed that bladder carcinogenesis is spanning 10-15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was primarily driven by {beta} mutations with high proliferative advantage. This is the first detailed molecular characterization of mucosal field effects initiating bladder carcinogenesis on the whole-organ scale. It provides novel insights into incipient phases of bladder carcinogenesis and biomarkers for early detection of bladder cancer as well as targets for preventive therapies.

genomics↗

bioRxiv2021

The M1 aminopeptidase NPEPPS is a novel regulator of cisplatin sensitivity

There is an unmet need to improve efficacy of platinum-based cancer chemotherapy. Using multi-omic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified Puromycin-Sensitive Aminopeptidase, NPEPPS, as a novel driver of cisplatin resistance. NPEPPS depletion sensitizes resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. We show that NPEPPS affects treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDOs) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin and they were found to be concordant with clinical response. In PDOs, shRNA depletion or pharmacologic inhibition of NPEPPS led to increased cisplatin sensitivity, while NPEPPS overexpression had the opposite effect. Our data present NPEPPS as a novel and druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations, along with providing the preclinical data to support clinical trials combining NPEPPS inhibition with cisplatin.

cancer biology↗