Biology subjects

Ali, E.

Publications and source records attributed to Ali, E..

6 recordsLinked to original sources

bioRxiv2024

Tracking clonal evolution of drug resistance in ovarian cancer patients by exploiting structural variants in cfDNA

Drug resistance is the major cause of therapeutic failure in high-grade serous ovarian cancer (HGSOC). Yet, the mechanisms by which tumors evolve to drug resistant states remains largely unknown. To address this, we aimed to exploit clone-specific genomic structural variations by combining scaled single-cell whole genome sequencing with longitudinally collected cell-free DNA (cfDNA), enabling clonal tracking before, during and after treatment. We developed a cfDNA hybrid capture, deep sequencing approach based on leveraging clone-specific structural variants as endogenous barcodes, with orders of magnitude lower error rates than single nucleotide variants in ctDNA (circulating tumor DNA) detection, demonstrated on 19 patients at baseline. We then applied this to monitor and model clonal evolution over several years in ten HGSOC patients treated with systemic therapy from diagnosis through recurrence. We found drug resistance to be polyclonal in most cases, but frequently dominated by a single high-fitness and expanding clone, reducing clonal diversity in the relapsed disease state in most patients. Drug-resistant clones frequently displayed notable genomic features, including high-level amplifications of oncogenes such as CCNE1, RAB25, NOTCH3, and ERBB2. Using a population genetics Wright-Fisher model, we found evolutionary trajectories of these features were consistent with drug-induced positive selection. In select cases, these alterations impacted selection of secondary lines of therapy with positive patient outcomes. For cases with matched single-cell RNA sequencing data, pre-existing and genomically encoded phenotypic states such as upregulation of EMT and VEGF were linked to drug resistance. Together, our findings indicate that drug resistant states in HGSOC pre-exist at diagnosis and lead to dramatic clonal expansions that alter clonal composition at the time of relapse. We suggest that combining tumor single cell sequencing with cfDNA enables clonal tracking in patients and harbors potential for evolution-informed adaptive treatment decisions.

cancer biology↗

bioRxiv2024

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime, we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily active mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

cancer biology↗

bioRxiv2022

Overexpression of Interleukin-8 and Interleukin-13 as potent immune markers associated with survival and dietary habits in esophageal squamous cell carcinoma.

BackgroundInterleukin-8 (IL8), Interleukin-12 (IL12) and Interleukin-13 (IL13) are cytokines that play regulatory role in cancer pathogenesis. We analysed their expression profile to evaluate as molecular biomarkers of esophageal squamous cell carcinoma (ESCC) and their association with different parameters. MethodsExpression analysis of IL8, IL12 and IL13 were performed by Real time qPCR in blood and tumor tissue of 120 ESCC patients. The expression profiles were associated with different clinicopathological and dietary factors. Survival and hazard analysis were also performed. ResultsWhen compared to normal controls, IL8 expression showed upregulation in 83% tissue samples (p=0.000) and 62% blood samples (p=0.388), IL12 expression showed upregulation in 62% tissue samples (p=0.435) and 57% blood samples (p=0.222) and IL13 expression showed upregulation in 83% tissue samples (p=0.001) and 68% blood samples (p=0.312). Significant positive correlation (p<0.05) was observed between tissue and blood level expression of IL8, IL12 and IL13. Different clinicopathological factors and dietary habits showed significant association (p<0.05) with IL8, IL12 and IL13 expression.. Statistically significant positive correlation were observed for IL8 and IL13 expression in tissue as well as IL13 and IL12 expression in both tissue and blood. Also significant negative correlation of IL8 and IL12 expression in blood and tissue were also observed. Tumor stage, node stage, metastasis, consumption of betel nut, tobacco, alcohol, hot food, smoked food, spices, IL8 expression in blood, IL13 expression in tissue and IL12 expression in blood and tissue showed significant association (p<0.05) with survival of ESCC patients. ConclusionsAltered expression of IL8, IL12 and IL13 may be associated with ESCC progression. Overexpression of IL8 and IL13 in tissue samples may be potential biomarkers for ECSS screening. Additionally, results from both survival and hazard analysis data indicate the effects of various parameters on the survival and mortality rate of ESCC patients.

immunology↗

bioRxiv2021

Proteomic insight into soybean response to flooding stress reveals changes in basic energy metabolism and cell wall modifications

Soybean is a legume crop enriched with proteins and oil. It is frequently exposed to anthropogenic and natural flooding that limits its growth and yield. Current study applied gel-free proteomic techniques to unravel soybean response mechanism to flooding stress. Two-days-old soybeans were flooded for 4 days continuously and root samples were collected at days 2 to 6 for proteomic and enzymatic analyses. Age-matched untreated soybeans were collected as control. After protein extraction, purification and tryptic digestion, the peptides were analyzed on nano-liquid chromatography-mass spectrometry. A total of 539 and 472 proteins with matched peptides 2 or more were identified in control and flooded seedlings, respectively. Among these 364 proteins were commonly identified in both control and flooded soybeans. Fourty-two proteins abundances were changed 4-fold after 2-days of flooding stress as compared to starting point. The cluster analysis showed that highly increased proteins included cupin family proteins, enolase, pectin methylesterase inhibitor, glyoxalase II, alcohol dehydrogenase and aldolase. The enzyme assay of enolase and pectin methylesterase inhibitor confirmed protein abundance changes. These findings suggest that soybean adopts the less energy consuming strategies and brings biochemical and structural changes in the cell wall to effectively respond to flooding stress and for the survival.

biochemistry↗

bioRxiv2020

De-novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

This year nearly 20,000 lives will be lost to Glioblastoma (GBM), a treatment-resistant primary brain cancer. In this study, we identified a molecular circuit driven by epigenetic regulation that regulates the expression of ciliary protein ALR13B. We also demonstrated that ARL13B subsequently interacts with purine biosynthetic enzyme IMPDH2. Removal of ARL13B enhanced TMZ-induced DNA damage by reducing de-novo purine biosynthesis and forcing GBM cells to rely on the purine salvage pathway. Furthermore, targeting can be achieved by using an FDA-approved drug, Mycophenolate Moefitil. Our results suggest a clinical evaluation of MMF in combination with TMZ treatment in glioma patients.

cancer biology↗

bioRxiv2017

A new method to isolate algal species from mix algal culture

To meet the issues of energy and environment, algae cultivation for biofuel and CO2 sequestration is getting popular at the global level. Specific algal strains have been identified for production of biofuel, biomolecules and biomass. To start algae cultivation at lab or industrial scale, it is requirement to have isolated and identified algal culture for targeted products. Water sample for algae from aquatic system is usually consist of mix culture of algae and need to be processed for targeted isolated algal strains using reported techniques like streaking, spraying, serial dilution, and single-cell isolations. But none of these techniques is considered as efficient or popular except streaking on agar plate which involves a set of microbial techniques and may take months to make isolation properly. Here, a new method is proposed to make alginic acid solution using aquatic sample followed by pouring it in calcium chloride solution drop by drop which makes the beads with single or more algal species trapped in each bead. The trapped algal species in the beads are grown in 96 wells plate having single bead in each well with standard medium leading to microscopic verification of the isolated algal species to process further. A mix culture from a lake was subjected to isolation using proposed method and excellent results were obtained in one week duration.

microbiology↗