Biology subjects

Seshadri, M.

Publications and source records attributed to Seshadri, M..

6 recordsLinked to original sources

bioRxiv2025

Oligodendrocytes show enriched expression of amyloid precursor protein and GABA B receptor isoform 1a

Amyloid precursor protein (APP) is a type I transmembrane protein that undergoes proteolytic processing to generate amyloid-{beta}, the main component of amyloid plaques found in brains with Alzheimers disease. The proteolytic processing of APP also generates soluble APP alpha (sAPP) which can modulate synaptic transmission and neurite outgrowth through the {gamma}-aminobutyric acid type B receptor (GABABR). Whether GABABR mediates functions of sAPP in other neural cell types such as glia remains unknown. sAPP binds the R1a subunit isoform of GABABR1 which contains two sushi domains absent in R1b. It is unclear whether both GABABR1 isoforms are expressed equally across brain cell types. We determined relative RNA levels of the GABABR1a and 1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed a GABABR1 isoform-specific RNAseq analysis workflow to probe a publicly available dataset. We also isolated five cell types from a single mouse brain and performed RT-qPCR. We show that the GABABR1a and 1b isoforms are differentially expressed among cell types. GABABR1a expression was highest in oligodendrocytes and GABABR1b expression was highest in astrocytes, suggesting that sAPP-mediated GABABR signaling may be most prominent in oligodendrocytes. We also confirmed that APP is expressed in all five cell types and showed that APP RNA levels are highest in oligodendrocytes. Together, our findings uncover cell type-specific expression of GABABR isoforms and highlight oligodendrocytes as a principal cell type for GABABR1a-mediated APP signaling, providing a foundation for future mechanistic studies.

neuroscience↗

bioRxiv2025

Reversible therapeutic resistance in EGFR mutant lung cancer caused by RB1 loss induced lineage plasticity

Treatment with EGFR tyrosine kinase inhibitors (EGFR TKI) is standard of care for patients with lung cancer initiated by activating mutations in the EGFR gene. While EGFR TKI treatment is effective, virtually all patients progress on therapy. Loss of function mutations in the RB1 tumor suppressor gene are associated with poor EGFR TKI outcomes, but underlying mechanisms remain unclear. Analysis of genetically engineered experimental models and human clinical specimens described here demonstrates RB1 loss has minimal impact on initial cell cycle responses to EGFR TKI but markedly accelerates acquired resistance over time. RB1 loss promotes transcriptional plasticity that enables rare cells to spontaneously assume reversible, resistance-conferring lineage states. These findings highlight the importance of non-genetic adaptations in driving acquired EGFR TKI resistance, advance our understanding of how RB1 impacts cancer, and identify opportunities to improve EGFR TKI treatment outcomes by targeting reversible epigenetic resistance mechanisms.

cancer biology↗

bioRxiv2022

TNF signaling is required for castration-induced vascular damage preceding prostate cancer regression

The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. Besides this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostate. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer micro-environment mediating prostate cancer regression following androgen deprivation. SIGNIFICANCEThese studies define TNF as the mediator of androgen deprivation therapy-induced functional and structural vascular damage in prostate tumors.

cancer biology↗

bioRxiv2021

Partial loss of succinate dehydrogenase reduces high red cell distribution width and promotes healthy survival in chronically hypoxic mice

Increased red cell distribution width (RDW), which measures erythrocyte size variability (anisocytosis), has been linked to early mortality in many diseases and normal aged population through unknown mechanisms. Hypoxia has been proposed to increase both RDW and mortality. However, experimental evidence, especially in animal models, is lacking. Here, we show that chronic hypobaric hypoxia (~10% O2) increases erythrocyte numbers, hemoglobin and RDW, while reducing longevity in male mice. Compound heterozygous knockout (chKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc and Sdhd reduce high RDW and immature reticulocyte fraction, and increase healthy lifespan in chronic hypoxia. Hemoglobin and erythrocyte numbers in hypoxia do not show statistically significant differences between Sdh chKO and WT mice. These results identify a mitochondrial mechanism regulating both RDW and organismal adaptation to chronic hypoxia, and suggest SDH as a potential therapeutic target to reduce high RDW-associated clinical mortality.

physiology↗

bioRxiv2019

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Pancreatic cancer harbors a poor prognosis due to the lack of effective systemic therapies. Here we interrogated means to target key effector pathways down-stream from KRAS. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumor progression. These effects were associated with stable cell cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumor and host that can contribute to durable control for tumors in combination with immune checkpoint inhibitor therapy.

cancer biology↗

bioRxiv2018

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

IntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.\n\nMethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.\n\nResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a private mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.\n\nConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.

neuroscience↗