Biology subjects

Ismail, W. M.

Publications and source records attributed to Ismail, W. M..

3 recordsLinked to original sources

bioRxiv2025

A Rare Multipotent Peg-like Epithelial Cell is a Candidate Cell-of-Origin for High-Grade Serous Ovarian Cancer

To illuminate the origins of high-grade serous ovarian cancer (HGSOC), the most lethal and common form of ovarian cancer, we have created a comprehensive living organoid biobank of human fallopian tube tissue, which is thought to be the origin of this cancer. Through optimized culture protocols and integrated multi-omic profiling--including single-cell RNA sequencing, chromatin accessibility (ATAC) analysis, proteomics, and secretomics--we assembled the largest molecular atlas of the fallopian tube epithelium to date. This resource revealed diverse epithelial lineages and regulatory networks, including a rare, multipotent epithelial subpopulation with hybrid epithelial-mesenchymal features. Spatially localized to the basal epithelium and resembling mesonephric developmental precursors, these cells exhibit transcriptomic and proteomic similarities to the mesenchyme-like subtype of HGSOC, implicating them as potential cells-of-origin. Their molecular identity is preserved in organoid models, enabling future mechanistic and translational studies. This resource, which advances fundamental understanding of epithelial hierarchy and cancer susceptibility, provides a platform to inform early detection and prevention strategies for aggressive forms of ovarian cancer. HighlightsO_LIEstablishment of a clinically annotated fallopian tube organoid biobank enables delineation of epithelial lineage hierarchies and differentiation capacity. C_LIO_LIMulti-omics integration defines robust, lineage-specific transcriptional and regulatory networks in the fallopian tube epithelium. C_LIO_LIA rare basal epithelial subpopulation with mesenchymal features aligns with a mesenchyme-like subtype of high-grade serous ovarian cancer. C_LIO_LIRare basal peg cells exhibit fetal mesonephric developmental transcriptional programs and are maintained ex-vivo in fallopian tube organoids. C_LI

cancer biology↗

bioRxiv2025

Single cell resolution of an epigenetic signature of persister tumor cell

Cancer can recur when a subset of tumor cells, denoted here as persister cells, are able to survive therapy and re-enter the cell cycle. The precise mechanisms that confer the persister state and whether it is characteristic of a subgroup of cells or arises from multiple cellular lineages remain poorly understood. We hypothesize that an epigenetic signature underlies the drug-tolerant persister state, characterized by transcriptional and chromatin accessibility changes that promote survival of residual cancer following chemotherapy. To identify clinically relevant features of persister cells in untreated tumors and residual disease, we performed single-cell multiomic profiling (snRNA+snATAC) on a cohort of non-malignant fallopian tube, treatment-naive, and neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) samples. We identified differences in gene expression and open chromatin between naive and residual patient tumors following chemotherapy. Although only a small proportion of the differentially expressed genes enriched in residual HGSOC overlapped with established gene sets for chemo-response and patient prognosis, the epigenomic analysis revealed activity of several DNA-binding factors that are both enriched upon chemotherapy and also high in resistant tumors prior to treatment. From this analysis, we identified an epigenetic signature that precedes expression and defines the persister state. This epigenetic signature also correlated with chemotherapy sensitivity and resistance using patient-derived xenograft models of HGSOC. Gene regulatory networks driven by the persister signature are involved in the activation of oncogenic pathways, including changes to the cell cycle promoting quiescence and stress response. Further study of the persister cells identified by this epigenetic signature may increase understanding of the mechanisms underlying persister cell survival and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence.

genomics↗

bioRxiv2022

Enhancer deregulation in TET2 Mutant Clonal Hematopoiesis is associated with increased COVID-19 related inflammation severity and mortality

DNMT3A and TET2 are epigenetic regulators commonly mutated in age related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematological neoplasms. While individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant CH on COVID-19-related cytokine release severity and mortality. Using single cell proteogenomics we show that DNMT3A mutations involve cells of myeloid and lymphoid lineages. Using single cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of IL32, a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Together, these data provide a mechanistic insight into the poor inflammatory outcomes seen in DNMT3A mutant CH patients infected with Sars-COV2.

genetics↗