Biology subjects

Arun, B.

Publications and source records attributed to Arun, B..

5 recordsLinked to original sources

bioRxiv2024

An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naive and longitudinal samples throughout neoadjuvant chemotherapy

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.

cancer biology↗

bioRxiv2024

Vesicle-mediated mitochondrial clearance underlies an actionable metabolic vulnerability in triple-negative breast cancer

Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies including triple-negative breast cancer (TNBC). Here, we aimed to identify the essential metabolic adaptations that support mitochondrial quality control with the goal to uncover actionable metabolic vulnerabilities with therapeutic potential. Using an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, coupled with functional experimental analyses, we define an alternative mechanism to mitophagy enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC that facilitates extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of the cancer cell sphingolipid onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-induced lethal mitophagy and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse model of TNBC. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.

cancer biology↗

bioRxiv2023

Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk in BRCA1 Mutation Carriers

Identifying pathogenic mutations and predicting their impact on protein structure, function and phenotype remain major challenges in genome sciences. Protein-folding chaperones participate in structure-function relationships by facilitating the folding of protein variants encoded by mutant genes. Here, we utilize a high-throughput protein-protein interaction assay to test HSP70 and HSP90 chaperone interactions as predictors of pathogenicity for variants in the tumor suppressor BRCA1. Chaperones bind 77% of pathogenic BRCA1-BRCT variants, most of which engaged HSP70 more than HSP90. Remarkably, the magnitude of chaperone binding to variants is proportional to the degree of structural and phenotypic defect induced by BRCA1 mutation. Quantitative chaperone interactions identified BRCA1-BRCT separation-of-function variants and hypomorphic alleles missed by pathogenicity prediction algorithms. Furthermore, increased chaperone binding signified greater cancer risk in human BRCA1 carriers. Altogether, our study showcases the utility of chaperones as quantitative cellular biosensors of variant folding and phenotypic severity. HIGHLIGHTSO_LIChaperones detect an abundance of pathogenic folding variants of BRCA1-BRCT. C_LIO_LIDegree of chaperone binding reflects severity of structural and phenotypic defect. C_LIO_LIChaperones identify separation-of-function and hypomorphic variants. C_LIO_LIChaperone interactions indicate penetrance and expressivity of BRCA1 alleles. C_LI

biochemistry↗

bioRxiv2019

Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

genetics↗

bioRxiv2018

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6x10-8), breast and ovarian cancer (rg=0.24, p=7x10-5), breast and lung cancer (rg=0.18, p=1.5x10-6) and breast and colorectal cancer (rg=0.15, p=1.1x10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

genomics↗