Biology subjects

Varghese, D.

Publications and source records attributed to Varghese, D..

4 recordsLinked to original sources

bioRxiv2026

AADAT-Driven Metabolic Control of Malate and CoQ10 Shapes Immune Evasion in Triple-Negative Breast Cancer

Compared to other subtypes of breast cancer, triple-negative breast cancers (TNBC) have fewer treatment options and exhibit a worse prognosis. Through integrated transcriptomic, metabolomic, immunohistochemical, spatial, and clinical analyses, we identify the mitochondrial enzyme, -aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT mRNA and protein were significantly upregulated in human TNBC, and high AADAT expression was associated with reduced intra-tumoral CD8 T-cell density and inferior survival. Genetic silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8 T-cell-dependent manner, enhanced effector T-cell activation, and sensitized tumors to dual PD-1/CTLA-4 blockade. Mechanistically, unbiased metabolomics showed increased malate levels after AADAT knockdown. Additionally, 4-hydroxyphenylpyruvate, an essential precursor for coenzyme Q10(CoQ10) biosynthesis, decreased following AADAT knockdown, suggesting an impaired mitochondrial electron transport chain. CoQ10 supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ10-supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8 T-cell oxidative metabolism, increased the NAD/NADH ratio and reactive oxygen species, and augmented TNF- and IFN-{gamma} production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti-PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival. In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8 T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC. Statement of SignificanceAADAT defines a metabolic-immune axis driving immune evasion and therapy resistance in triple-negative breast cancer. Blocking AADAT or administering oral malate reactivates CD8 T-cell immunity and sensitizes chemo-immunotherapy-resistant tumors to these agents. These findings uncover a readily translatable metabolic vulnerability with potential to improve outcomes for patients with aggressive breast cancer subtypes.

cancer biology↗

bioRxiv2025

CancerSTFormer enables multi-scale analysis of spot-resolution spatial transcriptomes and dissects the gene and immune regulatory responses of targeted therapies

The growing number of spot-resolution sequencing based spatial transcriptomic (ST) datasets provides an unprecedented opportunity to study multicellular spatial niches driving cancer transitions. However studying niche-level behavior of tumors remains challenging as it requires a multi-scale approach to modeling the spatial niches and the ability to predict possible effects of genetic perturbations on spatial niches. We propose CancerSTFormer, consisting of a pair of spatially aware transcriptomic foundation models to accommodate niche modeling at different length scales. These models, at the 50{micro}m-Local and 250{micro}m-Extended scales, possess unique capabilities to recover ligand-target gene relationships, niche-specific differentially expressed genes, and organ-specific metastasis associated genes in diverse cancer applications. CancerSTFormer can also reveal the regulatory effects of immune-checkpoint blockade therapies, and other targeted therapies, on patients tumors through perturbation analysis, and accurately recapitulated perturbation responses from a spatial Perturb-map experiment. By reusing existing spot-resolution ST studies at scale, this tool transforms the vast spot-resolution ST data into a resource for understanding how gene perturbation impact spatial niches in cancer, while also providing ST-driven, gene-based refinement of treatment-resistance and sensitivity signatures derived from existing bulk transcriptomic studies, enhancing signature interpretation.

bioinformatics↗

bioRxiv2025

Analysis of spectral and photosynthetic response variations of Cystoseira spp. exposed to Chromium

1.This study explores the physiological and spectral responses of different species belonging the genus Cystoseira to varying concentrations of chromium (Cr) in controlled experimental conditions. The research highlights the potential of Cystoseira spp. as a bioindicator for monitoring heavy metal pollution in marine ecosystems. Experiments were conducted in tanks with increasing chromium concentrations (0, 0.1, 1, and 10 {micro}mol l-{superscript 1}), analyzing changes in reflectance, photosynthetic efficiency, and pigment composition over 14 days. Results showed dose-and time-dependent effects, with higher chromium levels causing significant photosynthetic inhibition, oxidative stress, and chlorophyll degradation. Spectral analyses identified key wavelengths (550 nm and 710 nm) correlating with chromium-induced stress, supporting their use in remote sensing for environmental monitoring. The study underscores the importance of integrating field validation and remote sensing for large-scale monitoring of marine ecosystems impacted by heavy metal contamination. These findings contribute to conservation strategies and the development of innovative tools for assessing the ecological quality of coastal waters.

ecology↗

bioRxiv2024

Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma

Immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy. However, given the limited number of current targets, the identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potent in vitro activity among established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti-tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy is overall limited in ACC due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 is extremely potent and induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation. Single cell RNA-seq of ACC metastatic tumors reveals significantly decreased adrenocortical differentiation in DLK low or negative cells compared to DLK1 positive cells. This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial (NCT06041516).

cancer biology↗