Biology subjects

Datta, K.

Publications and source records attributed to Datta, K..

7 recordsLinked to original sources

bioRxiv2026

Does herbivore diversity increase induced phytochemical diversity? Testing the pathway co-activation hypothesis

The mechanistic link between multiple herbivory and phytochemical diversity as an emergent plant trait is poorly understood. Because alternative, interacting biosynthetic pathways enable high specificity of induced plant responses to different herbivores, we hypothesized that multi-species herbivory increases phytochemical diversity by simultaneously activating mutually-antagonistic response pathways. We tested this hypothesis using a dual-herbivory experiment with phloem-feeding aphids and leaf-chewing caterpillars on cabbage seedlings, combined with untargeted metabolomics. To isolate plant responses to herbivore identities from responses to damage levels, we equalized herbivory pressures across treatments. The underlying mechanism was tested using similar applications of the respective defense phytohormones. Phytochemical richness increased under dual-herbivory relative to single-species herbivory. Phytochemical evenness (2D diversity) increased from caterpillar-only to dual-herbivory. Phytohormone applications produced similar effects, supporting the hypothesized mechanism. Analyses of glucosinolate levels and whole-metabolome shifts were consistent with prevalent, but not exclusive, antagonistic JA-SA crosstalk, explaining the increased phytochemical evenness under combined exposures. The demonstrated general mechanistic basis suggests a broad positive relationship between phytochemical and herbivore diversity across plant-herbivore systems. Using a theoretical simulation model, we extend our two-species hypothesis to the community level. The ecological effects of herbivore-induced plasticity in phytochemical diversity may ultimately cascade through communities and food web interactions.

plant biology↗

bioRxiv2026

An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases.

Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/740121v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c641f1org.highwire.dtl.DTLVardef@113696aorg.highwire.dtl.DTLVardef@16dcc72org.highwire.dtl.DTLVardef@1898d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINovel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program. C_LIO_LIThis study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases. C_LIO_LIPDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models. C_LIO_LIPC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases. C_LI

cancer biology↗

bioRxiv2025

MAPT Splicing Modulators as a Therapeutic Strategy for Tauopathies

Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of microtubule-associated protein tau (MAPT) in the brain. These disorders, like frontotemporal dementia (FTD-Tau), currently lack effective therapies and can occur sporadically or be inherited when associated with MAPT gene mutations. The MAPT gene region encompassing exon 10 and adjacent introns is a hotspot for pathogenic variants, including splicing mutations that enhance exon 10 inclusion and increase 4R tau expression, and gain-of-function mutations that generate aggregation-prone mutant 4R tau protein. For these 4R-specific tauopathies, a targeted mRNA splicing approach that promotes exon 10 exclusion may offer therapeutic benefit. In this study, we discovered novel splicing modulator compounds (SMCs) that promote MAPT exon 10 exclusion, and demonstrated their efficacy in FTD patient-derived neuronal models carrying the tau-P301L gain-of-function mutation or the tau-S305N splicing mutation. Treatment with SMC reduced 4R tau expression and decreased the accumulation of hyperphosphorylated tau (pTau), oligomeric and insoluble tau, thereby rescuing tau-associated neuronal toxicity. Importantly, our lead SMC corrected the 3R/4R splice ratio in vivo and significantly reduced pTau in the brain of a gene- replacement (GR) mouse model expressing the human tau-N279K splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish MAPT pre- mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies. One Sentence SummaryDiscovery of SMCs that correct MAPT splicing, reduce 4R tau, and rescue pathology in patient- derived neuronal and in vivo models of 4R tauopathies.

neuroscience↗

bioRxiv2025

ECD, a novel androgen receptor target promotes prostate cancer tumorigenesis by regulating glycolysis

Androgen receptor (AR)-mediated signaling is essential for PC tumorigenesis. In the TCGA database we observed a positive correlation between ECD and AR expression. Consistently, Dihydrotestosterone (DHT) treatment of PC cell lines increased ECD mRNA and protein levels, and AR knockdown (KD) reduced ECD expression. Bioinformatic analysis predicted three consensus androgen response elements in the ECD promoter, and DHT treatment increased AR occupancy at the ECD promoter, and enhanced ECD promoter activity. Enzalutamide treatment decreased ECD levels, and ECD knockout (KO) in PC cells reduced oncogenic traits, suggesting a functional role of ECD to maintain PC oncogenesis. ECD mRNA and protein are overexpressed in PC patient tissues, and its overexpression predicts shorter survival. Overexpression of ECD in PC cell lines enhanced the oncogenic traits in vitro and developed faster and larger highly proliferative xenograft tumors. RNA-seq analysis of mouse tumors revealed an increase in mRNA levels of several glycolytic genes. ECD associates with mRNA of key glycolytic genes and is required for their stability, consistent with our recent demonstration of ECD is an RNA binding protein. Higher glucose uptake and glycolysis was seen upon ECD overexpression in PC cells. Together, we demonstrate the role of a novel AR target gene ECD in PC tumorigenesis.

cancer biology↗

bioRxiv2023

Regulation of Non-Canonical Proteins Encoded by Small Open Reading Frames via the Nonsense-Mediated Decay Pathway.

Immunotherapy interventions relies heavily on neoantigen availability. The human genome encodes non-canonical/mutant proteins that potentially contain neoantigenic peptides. Nevertheless, their typically low expression, potentially moderated by the Nonsense-Mediated Decay (NMD) pathway, restricts their therapeutic utility. In this study, we explored the NMD pathway influence on non-canonical/mutant protein expression, specifically focusing on UPF1 knockdown. We implemented proteogenomic approaches to ascertain if the encoding transcripts and their respective proteins were upregulated post-knockdown. Complementary to this, we conducted a comprehensive pan-cancer survey of UPF1 expression and an in vivo evaluation of UPF1 expression in Triple-Negative Breast Cancer (TNBC) tissue. Our empirical results delineated that UPF1 knockdown precipitates an increase in the transcription of non-canonical/mutant proteins, especially those originating from retained-introns, pseudogenes, long non-coding RNAs, and unannotated biotypes. Furthermore, the analysis revealed that UPF1 expression was conspicuously high across a range of neoplastic tissues, with protein levels notably amplified in patient derived TNBC tumours in comparison to adjacent tissues. Our study elucidates UPF1 functional role in attenuating transcriptional noise through the degradation of transcripts encoding non-canonical/mutant proteins. Interestingly, we observed an upregulation of the NMD pathway in cancer, potentially functioning as a "neoantigen masking" mechanism that subdues non-canonical/mutant protein expression. Suppressing this mechanism may unveil a new cadre of neoantigens accessible to the antigen presentation pathway. Our novel findings proffer a solid base for devising therapeutic strategies targeting UPF1 or the NMD pathway, given the pronounced presence of UPF1 in malignant cells, thus potentially augmenting immunotherapeutic responses in cancer.

cell biology↗

bioRxiv2023

Role of GD2 and its biosynthetic enzyme GD3 synthase in prostate cancer tumorigenesis

While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2high cell fraction was enriched upon growth of PC cells as tumorspheres and GD2high fraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2high CRPC cell models markedly impaired the in vitro oncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT) marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.

cancer biology↗

bioRxiv2021

IRC3 regulates mitochondrial translation in response to metabolic cues in Saccharomyces cerevisiae

Mitochondrial oxidative phosphorylation (OXPHOS) enzymes are made up of dual genetic origin. Mechanism regulating expression of nuclear encoded OXPHOS subunits in response to metabolic cues (glucose vs. glycerol), is significantly understood while regulation of mitochondrially encoded OXPHOS subunits is poorly defined. Here, we show that IRC3 a DEAD/H box helicase, previously implicated in mitochondrial DNA maintenance, is central to integrating metabolic cues with mitochondrial translation. Irc3 associates with mitochondrial small ribosomal subunit in cells consistent with its role in regulating translation elongation based on Arg8m reporter system. Glucose grown{Delta} irc3{rho}+ and irc3 temperature sensitive cells at 37C have reduced translation rates from majority of mRNAs. In contrast, when galactose was the carbon source, reduction in mitochondrial translation was observed predominantly from Cox1 mRNA in{Delta} irc3{rho}+ but no defect was observed in irc3 temperature sensitive cells, at 37C. In support, of a model whereby IRC3 responds to metabolic cues, suppressors of {Delta}irc3 isolated for restoration of growth on glycerol media restore mitochondrial translation differentially in presence of glucose vs. glycerol.

cell biology↗