Biology subjects

Mallya, S.

Publications and source records attributed to Mallya, S..

6 recordsLinked to original sources

bioRxiv2025

PHLDA2 promotes breast cancer metastasis by co-opting a developmental program for placental vascular remodeling

Identifying drivers of metastasis is essential for developing new treatments for patients with advanced disease. Here, we identify PHLDA2 as a robust driver of breast cancer metastasis. Previous work established PHLDA2 as an imprinted gene expressed by trophoblasts which are critical for vascular remodeling during placental development. We find that hypomethylation of PHLDA2 in breast tumors correlates with increased gene expression, which is associated with metastasis and poor survival in breast cancer patients. RNA-sequencing showed that PHLDA2 overexpression results in upregulation of genes that control invasion, extracellular matrix assembly, and vascular remodeling, consistent with trophoblast functions in placental development. Using an in vitro vascularized microtumor (VMT) system, we find that PHLDA2 functions through SPARC, which promotes metastasis by inducing vascular permeability and enhancing tumor dissemination. These data suggest that increased expression of PHLDA2 through hypomethylation promotes metastasis by ectopic expression of a developmental program for vascular remodeling.

cancer biology↗

bioRxiv2024

Mitochondrial genome-encoded mitomiRs regulate cellular plasticity and susceptibility to ferroptosis in triple-negative breast cancer

Ferroptosis is a distinct form of regulated cell death promoted by iron-dependent lipid peroxidation. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. Although mitochondrial dysfunction contributes to metabolic reprogramming in cancer cells, its role in ferroptosis remains to be identified. We identified that the mitochondrial genome encodes 13 miRNAs (mitomiRs) that are highly expressed in breast cancer cell lines and patient-derived tumor samples. Expression analysis revealed that mitomiRs are upregulated in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Interestingly, 11 out of the 13 mitomiRs bind to the 3'UTR of zinc finger E-box-binding homeobox 1 (ZEB1), a transcription factor, involved in epithelial to mesenchymal transition (EMT) in breast cancer. Using mitomiR-3 mimic, inhibitor and sponges, we confirmed that mitomiR-3 indeed regulate ZEB1 expression in TNBC cells. Increased mesenchymal features in TNBC contributed to vulnerability to pro-ferroptotic metabolic reprogramming sensitizing to cell death in in vitro and in vivo models. Some of the challenges associated with pro-ferroptotic drugs includes lack of cancer cell specificity, low targeting ability, normal tissue toxicity contributing to their limited clinical application as cancer therapeutics. Here, we identified mitomiRs which are highly expressed in TNBC subtypes with low expression in normal breast cells making them an ideal candidate for selective inhibition for targeted therapy. Further, we demonstrated that the inhibition of mitomiRs in triple-negative breast cancer cells promote pro-ferroptotic metabolic reprogramming which can be exploited as novel vulnerability for targeted ferroptotic induction in cancer cells avoiding the normal tissue toxicity. Collectively, our results indicate a novel mechanism of mitochondrial miRNA mediated ferroptosis sensitivity in TNBC subtypes which could be exploited to develop potential miRNA-based therapeutics.

cancer biology↗

bioRxiv2024

Novel nanopore sequencing method for determining Human Papillomavirus integrations in tumors without the need for whole genome sequencing

Human papillomaviral (HPV) integrations into host human genome, a key event in cervical carcinogenesis, are currently mapped through laborious and expensive sequencing methodologies. We developed and validated a novel library preparation strategy for nanopore sequencing to generate long targeted reads with HPV and human chimeric sequences. Using this strategy, we validated known HPV integrations in HeLa (HPV18) and SiHa (HPV16) cell lines. We also mapped integration sites in five HPV+ cervical cancer patients, which were confirmed by whole genome and Sanger sequencing. Our nanopore-based method provides a precise and efficient strategy to capture HPV integrations crucial for understanding tumorigenesis.

genomics↗

bioRxiv2023

Low-dose exposure to malathion and radiation culminates in the dysregulation of multiple neuronal processes instigating neurotoxicity and activation of neurodegeneration pathways in mice hippocampus

Neurodegenerative disorders are a debilitating and persistent threat to the global elderly population carrying grim outcomes. Their genesis is often multifactorial, with a history of early exposure to xenobiotics like pesticides or diagnostic exposure to ionizing radiation. A holistic molecular insight into their mechanistic induction is still unclear upon single or combinatorial exposure to different toxicants. In the present study, one-month-old C57/BL-6J male mice were treated orally with malathion (MAL) (50mg/kg body wt. for 14 days) and/or a single whole-body radiation (IR) (0.5 Gy) on the 8th day. Post-treatment, behavioral assays were conducted to assess exploratory behavior, memory, and learning. Following sacrifice, brains were collected for histology, biochemical assays, and transcriptomic analysis. Differential expression analysis, Gene ontology, and pathway enrichment revealed several common and uniquely altered genes, biological processes, and pathways related to neurodegeneration, synaptic transmission and plasticity, neuronal survival, proliferation, and regulation of neuronal death. Increased astrogliosis was observed in the IR and co-exposure groups, with significant neuronal cell death and reduction in the expression of NeuN in all three groups. Sholl analysis and dendritic arborization/ spine density study revealed decreased total apical neuronal path length and dendritic spine density in all three groups. Decreased levels of antioxidant enzymes GST and GSH and acetylcholinesterase enzyme activity were also detected. However, there were no changes in exploratory behavior or learning and memory. Thus, explicating the molecular mechanisms behind MAL and IR can provide novel insights into the genesis of environmental factor-driven neurodegenerative pathogenesis.

neuroscience↗

bioRxiv2023

MiR-4521 perturbs FOXM1-mediated DNA damage response in breast cancer

Forkhead (FOX) transcription factors are involved in cell cycle control, cellular differentiation, maintenance of tissues, and aging. Mutation or aberrant expression of FOX proteins is associated with developmental disorders and cancers. FOXM1, an oncogenic transcription factor, is a promoter of cell proliferation and accelerated development of breast adenocarcinomas, squamous carcinoma of the head, neck, and cervix, and nasopharyngeal carcinoma. High FOXM1 expression is correlated with chemoresistance in patients treated with doxorubicin and Epirubicin by enhancing the DNA repair in breast cancer cells. Here, we showed that FOXM1 is a direct target of miR-4521 in breast cancer. Overexpression of miR-4521 significantly downregulated FOXM1 expression in breast cancer cells. FOXM1 regulates cell cycle progression and DNA damage response in breast cancer. We showed that miR-4521 expression leads to increased ROS levels and DNA damage in breast cancer cells. FOXM1 plays a critical role in ROS scavenging and promotes stemness which contributes to drug resistance in breast cancer. We observed that breast cancer cells stably expressing miR-4521 lead to cell cycle arrest, impaired FOXM1 mediated DNA damage response leading to increased cell death in breast cancer cells. Additionally, miR-4521-mediated FOXM1 downregulation perturbs cell proliferation, invasion, cell cycle progression, and epithelial-to-mesenchymal progression (EMT) in breast cancer. High FOXM1 expression has been associated with radio and chemoresistance contributing to poor patient survival in multiple cancers, including breast cancer. Our study showed that FOXM1 mediated DNA damage response could be targeted using miR-4521 mimics as a novel therapeutic for breast cancer.

cancer biology↗

bioRxiv2022

Unique role for caspase-8 in the release of IL-1β and active caspase-1 from viable human monocytes during Toxoplasma gondii infection

Monocytes are among the first cells recruited to sites of infection and major producers of the potent proinflammatory cytokine IL-1{beta}. We previously showed that IL-1{beta} release during Toxoplasma gondii infection of primary human monocytes requires the NLRP3 inflammasome and caspase-1 activity but is independent of gasdermin D and pyroptosis. To investigate potential mechanisms of pyroptosis-independent release of IL-1{beta} during T. gondii infection, we constructed caspases-1, -4, -5, or -8 knockout THP-1 monocytic cells. Genetic ablation of caspase-1 or -8, but not caspase-4 or -5, decreased IL-1{beta} release during T. gondii infection without affecting cell death. In contrast, TNF- and IL-6 secretion were unperturbed in caspase-8 knockout cells during T. gondii infection. Dual pharmacological inhibition of caspase-8 and RIPK1 in primary monocytes also decreased IL-1{beta} release without affecting cell viability or parasite infection efficiency. In addition, caspase-8 was required for the release of active caspase-1 from T. gondii-infected cells and for IL-1{beta} release during infection with the related apicomplexan parasite Neospora caninum. Surprisingly, caspase-8 was dispensable for the synthesis and cleavage of IL-1{beta}, but caspase-8 deficiency resulted in the retention of mature IL-1{beta} within cells. Our data indicate that during T. gondii infection of human monocytes, caspase-8 functions in a novel gasdermin D-independent mechanism controlling IL-1{beta} release from viable cells. This study expands on the known molecular pathways that promote IL-1{beta} in human immune cells and provides the first evidence of a role for caspase-8 in the mechanism of IL-1{beta} release during host defense against infection.

immunology↗