Biology subjects

Narta, K.

Publications and source records attributed to Narta, K..

4 recordsLinked to original sources

bioRxiv2025

XenoSignal: Investigating Intra- and Inter-Species Ligand-Receptor Interactions Using AlphaFold3

Xenograft models, in which human tumors are implanted into mouse hosts, offer a unique platform to study tumor-microenvironment (TME) interactions. Ligand-receptor (LR) interactions are central to intercellular communication in this context, but most inference tools rely on single-species databases and assume conserved function across orthologues. To test whether this assumption holds given sequence and structural divergence, we developed XenoSignal, a computational framework that integrates AlphaFold3 structural predictions to assess the plausibility of intraspecies and interspecies LR interactions. The pipeline predicts whether human-mouse orthologues retain or lose their functional interaction, enabling construction of a high-confidence cross-species LR resource. XenoSignal facilitates the interpretation of tumor-TME crosstalk in xenografts and prioritizes LR pairs for experimental validation. This resource enhances our ability to dissect interspecies signaling, uncover mechanisms of immune evasion, and identify candidate therapeutic targets in translational cancer models.

bioinformatics↗

bioRxiv2025

Compound Delivery of eVLPs Enhances Prime Editing for Targeted Genome Engineering and High-Throughput Screening

Engineered virus-like particles (eVLPs) enable transgene-free ribonucleoprotein delivery for genome editing applications, yet optimized delivery strategies for high-throughput applications remain unexplored. Prime editing enables precise genomic modifications but suffers from limited efficiency that constrains its widespread adoption. Here, we present PRIME-VLP (Progressive Repeated Infections for Maximized Editing via Virus-Like Particles), a delivery strategy that enhances prime editing efficiency for both targeted genome engineering and high-throughput prime editing screening. PRIME-VLP leverages the temporal dynamics of eVLP-mediated editing through multiple sequential transductions with sub-saturating eVLP doses delivered at optimal intervals. This approach achieves 1.5 to 2.8-fold improvements in editing efficiency across diverse genomic targets and cell types. PRIME-VLP maintains high specificity without increasing off-target effects, compromising cellular viability or causing transcriptional perturbations. By decoupling pegRNA and editor delivery through pegRNA-free eVLPs, PRIME-VLP enables pooled prime editing screens, circumventing transgene silencing limitations of conventional lentiviral-based screens. Using a 6,000-pegRNA library targeting TP53, PRIME-VLP achieved 2.8-fold higher editing efficiency and improved reproducibility compared to conventional lentiviral delivery. An eVLP-based screen identified functional TP53 loss-of-function variants that confer resistance to MDM2 inhibition by Nutlin-3. This work expands the versatility of eVLPs beyond their current in vivo therapeutic applications, demonstrating their promise for high-throughput functional genomics by overcoming the delivery limitations of lentiviral systems.

genomics↗

bioRxiv2023

Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma

Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Towards this goal, we applied a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion were aligned with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs were highly prognostic in GBM patients. The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of immediate and long-term consequences of such perturbations, including identification of compensatory programs that will inform improved combinatorial therapies.

cancer biology↗

bioRxiv2022

Whole exome-sequencing of vitiligo lesions indicate lower burden of somatic variations: implications in risk for non-melanoma skin cancers

Mapping of somatic variations has enabled understanding the progression of clonal variations from healthy skin to cutaneous malignancies. Highlighting, the adaptive nature of pigmentation, germline mutations in albinism amplify skin cancer susceptibility. However, lower incidence of non-melanoma skin cancer among subjects with acquired depigmenting skin disorder vitiligo is enigmatic and a matter of longstanding debate. To address this, we performed high-coverage exome sequencing of matched non-lesional and lesional vitiligo skin along with whole blood to account for germline variations. Our analysis suggests lower burden of somatic cancer-associated variations in exposed depigmented lesional skin compared to the non-lesional skin. A detailed investigation of vitiligo skin transcriptome reveals elevation of DNA repair and cell-proliferation pathways. Validation by comet-assay for DNA damage and cell cycle analysis of epidermal cells suggest undamaged DNA in vitiligo lesions that could be attributed to higher proliferation-coupled repair. Endorsing this, UV-signature variations are not prominent, instead SBS5 associated with endogenous mutational processes is conspicuous in both the vitiligo tissues. Our systematic pilot study indicates lower somatic mutation burden in vitiligo skin and supports the earlier demographic observation on lower risk of non-melanoma skin cancer in vitiligo subjects, providing an opportunity to learn strategies for cancer prevention from vitiligo. Brief SummaryVitiligo skin harbors decreased somatic variation burden in cancer-associated genes and a concomitant augmentation in DNA repair response, explaining the lower incidence of cutaneous malignancies.

genomics↗