Biology subjects

Naik, P.

Publications and source records attributed to Naik, P..

6 recordsLinked to original sources

bioRxiv2026

PTP1B supports survival and regulates CFL1 and HSP90a abundance in trastuzumab-resistant HER2-positive breast cancer.

Trastuzumab resistance limits the treatment of HER2-positive breast cancer. Here, we identify protein tyrosine phosphatase 1B (PTP1B) as a survival dependency in models of intrinsic and acquired trastuzumab resistance, including cells with endogenous ERBB2 kinase domain mutations (L755S and V777L), a patient-derived tumor organoid model, and orthotopic xenografts. PTP1B expression was elevated in multiple trastuzumab-resistant models, accompanied by increased PI3K-AKT and ERK signaling in several of these. The PTP1B inhibitor DPM-1003 suppressed growth of trastuzumab-resistant cells and organoids, inhibited xenograft progression, and induced apoptosis. Genetic ablation of PTP1B reduced growth and restored trastuzumab responsiveness in multiple resistance models, although JIMT1 cells remained resistant. Quantitative phosphoproteomics, phosphotyrosine immunoprecipitation, and substrate-trapping assays identified cofilin-1 (CFL1) and HSP90 as substrates of PTP1B. Loss of PTP1B increased their tyrosine phosphorylation, reduced their abundance, and increased their recovery in ubiquitin pull-downs. Proteasome inhibition restored substrate abundance, and PTP1B re-expression restored protein levels in PTP1B-null cells. These findings support a model in which PTP1B-dependent dephosphorylation limits turnover of the substrates CFL1 and HSP90. Genetic or pharmacological targeting of PTP1B suppressed survival-associated signaling and increased apoptotic markers. Together, these results identify PTP1B as a therapeutic vulnerability in trastuzumab-resistant HER2-positive breast cancer and implicate regulation of CFL1 and HSP90 abundance in the accompanying signaling response.

cancer biology↗

bioRxiv2026

Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression

Long non-coding RNAs (lncRNAs) have emerged as key regulators of tumor biology, however, thus far none have translated to cancer therapies. The lncRNA MALAT1 is overexpressed in more than 20 cancers, including breast cancer and has been shown to function via various mechanisms in a context-dependent manner, in 2D cell lines and mouse models. However, its functional role and therapeutic potential have not been evaluated in clinically relevant patient-derived models. We investigated the therapeutic potential of MALAT1-targeting antisense oligonucleotides (ASOs) for breast cancer, using clinically relevant 3D human patient-derived organoids (PDOs) and PDO-xenograft (PDO-X) models. We systematically evaluated the efficiency of MALAT1-targeting ASOs using a biobank of 28 PDO models. Across three independent PDO-X models of triple negative breast cancer (TNBC), MALAT1 depletion reproducibly drove widespread alternative splicing changes across all event types, with an enrichment of intron retention. Differentially spliced transcripts were enriched for targets of shared cancer-associated transcription factors, and MALAT1 knockdown specifically altered the relative abundance of previously unannotated splicing isoforms. Beyond tumor-intrinsic effects, tumor-specific MALAT1 depletion induced a consistent reduction in macrophage-associated gene signatures and reduced lung metastatic burden. Our data defines MALAT1s multifaceted role in TNBC, coordinating alternative splicing, tumor-stroma crosstalk, and metastatic progression. Our study provides strong preclinical evidence supporting MALAT1-targeted ASO therapy and establishes PDO-X models as a clinically relevant platform for functional interrogation of TNBC therapies. SignificanceUsing clinically relevant human PDO-X models, we show that MALAT1 influences alternative splicing, metastatic potential and the tumor microenvironment. These data support the potential of oncogenic lncRNA MALAT1 as a therapeutic target.

cancer biology↗

bioRxiv2025

Sensory neuronal mTORC1 signaling establishes neuroimmune memory that initiates allergic immunity

Environmental allergens are enriched in protease activity, a feature that directly activates cutaneous sensory neurons, triggering itch and Substance P release, which promotes Th2-skewing CD301b+ dendritic cell migration and initiates allergic immunity. However, allergens are typically encountered as repeated, subthreshold exposures, and how these cumulatively induce sensitization is unknown. We identify a sensory neuron-intrinsic mechanism of neuroimmune memory that enables this process. Initial activation by protease allergens induces sustained mTORC1 signaling and PGC-1-associated mitochondrial remodeling, establishing a metabolically primed state that amplifies neuroimmune responses upon allergen re-exposure. This heightened state, independent of adaptive immunity, drives enhanced itch, increased CD301b+ dendritic cell migration, and augmented Th2 differentiation. Disrupting neuronal mTORC1 signaling or mitochondrial stability abrogates this amplification while leaving primary responses intact. Importantly, this mechanism generalizes across distinct protease allergens, revealing mTORC1-driven metabolic reprogramming in sensory neurons as a form of innate neuroimmune memory underlying allergen cross-sensitization and polysensitization.

immunology↗

bioRxiv2023

Identification of glioblastoma stem cell-associated lncRNAs using single-cell RNA-sequencing datasets

Glioblastoma multiforme (GBM) is an aggressive, heterogeneous grade IV brain tumor. Glioblastoma stem cells (GSCs) initiate the tumor and are known culprits of therapy resistance. Mounting evidence has demonstrated a regulatory role of long non-coding RNAs (lncRNAs) in various biological processes, including pluripotency, differentiation, and tumorigenesis. A few studies have suggested that aberrant expression of lncRNAs is associated with GSCs. However, a comprehensive single-cell analysis of the GSC-associated lncRNA transcriptome has not been carried out. Here, we analyzed recently published single-cell RNA-sequencing datasets of adult human GBM tumors, GBM organoids, GSC-enriched GBM tumors, and developing human brains to identify lncRNAs highly expressed in GBM. To categorize GSC populations in the GBM tumors, we used the GSC marker genes SOX2, PROM1, FUT4, and L1CAM. We found three major GSC population clusters: radial glia, oligodendrocyte progenitor cells, and neurons. We found 10-100 lncRNAs significantly enriched in different GSC populations. We also validated the level of expression and localization of several GSC-enriched lncRNAs using qRT-PCR, single-molecule RNA FISH, and sub-cellular fractionation. We found that the radial glia GSC-enriched lncRNA PANTR1 is highly expressed in GSC lines and is localized to both the cytoplasmic and nuclear fractions. In contrast, the neuronal GSC-enriched lncRNAs LINC01563 and MALAT1 are highly enriched in the nuclear fraction of GSCs. Together, this study identified a panel of uncharacterized GSC-specific lncRNAs. These findings set the stage for future in-depth studies to examine their role in GBM pathology and their potential as biomarkers and/or therapeutic targets in GBM.

cancer biology↗

bioRxiv2021

Patient-derived triple negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, and an unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDOs) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBCs). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, our study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. Statement of SignificanceA comprehensive analysis of TNBC patient-derived organoids is presented by genomic, transcriptomic, and in-vivo analyses, providing insights into cellular heterogeneity and mechanisms of tumorigenesis at the single cell level.

cancer biology↗

bioRxiv2019

An integrated one-step assay combining thermal lysis and loop-mediated isothermal DNA amplification (LAMP) in 30 min from E. coli and M. smegmatis cells on a paper substrate

Developing sensors in the domains of food safety, soil analysis, water quality monitoring and healthcare often requires distinguishing between different species of bacteria. The most rapid, sensitive and specific method to identify bacteria is by analysing their DNA sequence, which comprises of disinfection and lysis of bacterial cells, amplification of the isolated DNA and detection of the amplified sequence. Seamless integration of these assays on a paper substrate remains a big challenge in paperfluidic nucleic acid analyis. Combining lysis and isothermal amplification in a single reaction step is difficult because the porosity of paper and the presence of cell debris following lysis reduces the efficiency of DNA amplification. On the other hand, extracting and purifying the DNA after lysis to improve the amplification efficiency involves addition of chemical reagents, one or more wash steps and manual intervention. This problem is even more complex for mycobacteria as its thick cell wall structure impedes lysis and the high GC-content of the genome requires careful optimization of enzymatic denaturation during isothermal amplification. Here we successfully combine thermal lysis and loop-mediated isothermal amplification (LAMP) into a single reaction step on paper without the need for any intermediate intervention. We demonstrate our integrated assay by amplifying DNA from 100 CFU/mL of Escherichia coli (MG1655) and Mycobacterium smegmatis (mc2155) cells in 30 min on a paper substrate. We also confirm that E. coli and M. smegmatis can be completely disinfected on paper by heating at 60 {degrees}C for 5 min and 15 min respectively, making this assay safe and suitable for incorporation into diverse paperfluidic sensors for field use.\n\nElectronic Supplementary Information (ESI) is available.

bioengineering↗