Biology subjects

Manas, A.

Publications and source records attributed to Manas, A..

8 recordsLinked to original sources

bioRxiv2025

Repurposing statins and phenothiazines to treat chemoresistant neuroblastoma.

Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through a dual-hit mechanism and induced a phenotypic switch towards an adrenergic cell state accompanied by increased sensitivity to chemotherapy. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma. TeaserUsing in silico prediction tools we repurposed statins and phenothiazines as a combination with translational potential in high-risk neuroblastoma.

cancer biology↗

bioRxiv2024

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

cell biology↗

bioRxiv2022

DNARecords: An extensible sparse format for petabyte scale genomics analysis

Recent growth in population scale sequencing initiatives involve both cohort scale and proportion of genome surveyed, with a transition from genotyping arrays to broader genome sequencing approaches. The resulting datasets can be challenging to analyze. Here we introduce DNARecords a novel sparse-compatible format for large scale genetic data. The structure enables integration of complex data types such as medical images and drug structures towards the development of machine learning methods to predict disease risk and drug response. We demonstrate its speed and memory advantages for various genetics analyses. These performance advantages will become more pronounced as it becomes feasible to analyze variants of lower population allele frequencies. Finally, we provide an open-source software plugin, built on top of Hail, to allow researchers to write and read such records as well as a set of examples for how to use them.

genomics↗

bioRxiv2022

Inherent evolutionary unpredictability in cancer model system

Despite the advent of personalized medicine, it is still difficult to predict how a cancer develops over time at the level of the individual patient or even in cancer model systems which begs the question whether certain aspects of cancer can ever be predicted or if there is an inherent unpredictability in cancer, similar to other complex biological systems, We demonstrate by a combination of agent-based mathematical modelling and analysis of data from patient-derived xenograft systems from multiple cancer types that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer cells. Our findings indicate that under those conditions, the cancer genome behaves as a complex dynamic system, making its long-term evolution inherently unpredictable.

evolutionary biology↗

bioRxiv2022

Clinically-relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance

Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB), an aggressive pediatric solid tumor of the sympathetic nervous system. Here, we developed a clinically-relevant in vivo treatment protocol mimicking the first line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN-amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal the genetic and non-genetic mechanisms involved in NB chemoresistance. We observed convergent and parallel evolution of key NB genetic aberrations over time. Intrinsic resistance to chemotherapy was associated with high genetic diversity and an embryonic phenotype. Relapsed NB PDX tumors with acquired resistance showed an immature mesenchymal-like phenotype resembling multipotent Schwann cell precursors that are found in the adrenal gland. NBs with a successful treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts, reduced cell cycle gene expression, and negative regulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states ex vivo. This work sheds light on mechanisms involved in NB chemotherapy response in vivo and ex vivo using a clinically-relevant protocol, and emphasizes the importance of transcriptional cell states in treatment response. Detailed characterization of resistance mechanisms is essential for the development of novel treatment strategies in non-responsive or relapsed high-risk NB. One Sentence SummaryCOJEC chemotherapy treatment of neuroblastoma PDX models uncovers patterns of transcriptional plasticity and chemoresistance.

cancer biology↗

bioRxiv2021

Engineering of human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia and solid tumor metastasis

The bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Pre-clinical research relies on xenograft mouse models, precluding the human-specific functional interactions of stem cells with their bone marrow microenvironment. Human mesenchymal cells can be exploited for the in vivo engineering of humanized ossicles (hOss). Those mini-bones provide a human niche conferring engraftment of human healthy and malignant blood samples, yet suffering from major reproducibility issue. Here, we report the standardized generation of hOss by developmental priming of a custom-designed human mesenchymal cell line. We demonstrate superior engraftment of cord blood hematopoietic cells and primary acute myeloid leukemia samples, but also validate our hOss as metastatic site for breast cancer cells. Finally, we report the first engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically reported osteolytic lesions. Collectively, our hOss constitute a powerful standardized and malleable platform to model normal hematopoiesis, leukemia and solid tumor metastasis.

bioengineering↗

bioRxiv2020

Detection of melanin-mediated false-positive for BaxΔ2 immunohistochemical staining in human skin tissue

Bax{Delta}2 is a pro-apoptotic isoform of the Bax family. We have previously shown that Bax{Delta}2 protein expression is low in most healthy human tissues with the protein mainly scattered in the connective tissues. Surprisingly, in skin tissue, the Bax{Delta}2-positive staining was strikingly strong, especially in the basal layer of the epidermis. It has been documented that melanin in the basal cells displays a brown color that could give false-positive staining in the commonly used DAB-based (3-3-diaminobenzidine) immunostaining. To avoid the false-positive staining from DAB-melanin, we performed immunofluorescent staining on the same set of tissues which were positive for Bax{Delta}2 in the DAB immunostaining. The results from co-immunofluorescent staining of Bax{Delta}2 and a basal cell marker CK-14 showed that the previously detected DAB-stained Bax{Delta}2-positive epidermal cells were CK-14 positive but Bax{Delta}2 negative. Consistent with our previous finding, the Bax{Delta}2-positive cells in the dermis connective tissues are positive in both DAB-based and fluorescence-based immunostainings. These data indicate that the DAB-stained Bax{Delta}2 positive cells in the basal layer of skin tissue are false-positive due to a misinterpretation of the melanin color, but the dermal connective tissue still presents real Bax{Delta}2 positive staining.

cell biology↗

bioRxiv2018

Detection of Pro-apoptotic BaxΔ2 Proteins in the Human Cerebellum

Bax{Delta}2 is a pro-apoptotic protein originally discovered in colon cancer patients with high microsatellite instability. Unlike most pro-apoptotic Bax family members, Bax{Delta}2 mediates cell death through a non-mitochondrial caspase 8-dependent pathway. In the scope of analyzing the distribution of Bax{Delta}2 expression in human tissues, we examined a panel of human brain samples. Here, we report 4 cerebellar cases in which the subjects had no neurological disorder or disease documented. We found Bax{Delta}2 positive cells scattered in all areas of the cerebellum, but most strikingly concentrated in Purkinje cell bodies and dendrites. Two out the four subjects tested had strong Bax{Delta}2- positive staining in nearly all Purkinje cells; one was mainly negative; and one had various levels of positive staining within the same sample. Further genetic analysis of the Purkinje cell layer, collected by microdissection from two subjects, showed that the samples contained G7 and G9 Bax microsatellite mutations. Both subjects were young and had no diseases reported at the time of death. As the distribution of Bax{Delta}2 is consistent with that known for Baxa, but in a less ubiquitous manner, these results may imply a potential function of Bax{Delta}2 in Purkinje cells.

cell biology↗