Biology subjects

Ziman, B.

Publications and source records attributed to Ziman, B..

9 recordsLinked to original sources

bioRxiv2026

A novel multicellular model of the adult mouse sinoatrial node retains spontaneous electrical activity and enables live investigation of the S100B-associated cell population

Approximately half of the adult sinoatrial node (SAN) consists of non-myocyte populations, indicating that cardiac pacemaking depends on interactions within a multicellular tissue rather than on pacemaker cardiomyocytes alone. Among these, an S100B-associated cell population has been implicated in pacemaker function, yet its identity and physiological roles remain poorly understood. These cells are rare and dispersed throughout the small, structurally complex SAN, making them difficult to observe repeatedly while preserving the native multicellular environment. Here, we established a dissociated multicellular culture of adult mouse SAN tissue on soft collagen-gelatin hydrogels that retains spontaneous electrical activity and permits longitudinal live imaging of S100B-associated cells. Using an S100B-EGFP+ reporter, we identified at least six reproducible morphological and behavioral phenotypes, including migration, proliferation, phagocytic behavior, and spontaneous self-organization into three-dimensional clusters. Cultures remained spontaneously electrically active for more than 10 days in vitro, with peak activity around day 10. This multicellular culture model bridges the gap between intact SAN preparations and isolated-cell cultures, allowing repeated observation of rare S100B-associated cells within a spontaneously active multicellular environment. HighlightsO_LIThe platform enables longitudinal live imaging of rare S100B-associated cells within an diverse multicellular SAN culture. C_LIO_LILive imaging reveals at least six reproducible morphological and behavioral phenotypes of S100B-associated cells. C_LIO_LIDissociated multicellular SAN cultures remain spontaneously electrically active for more than 10 days in vitro. C_LI

cell biology↗

bioRxiv2025

ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion

Transcriptional Intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers, yet how transcriptional ITH programs drive tumor metastasis and immune evasion in upper aerodigestive squamous cell carcinoma (UASCC) remains unclear. Through single-cell RNA sequencing analysis of UASCC cells and patient tumors, we uncovered a hybrid epithelial mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating both STAT1 and PD-L1 (CD274) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, ETS1-high tumors strongly correlated with poor survival and resistance to immune checkpoint blockade across multiple cohorts. Leveraging drug screens, we discovered that ETS1-high cancers are vulnerable to HSP90 inhibitors (e.g., Alvespimycin), which suppress ETS1 by disrupting HIF1A-mediated transcriptional activation. Together, our work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.

cancer biology↗

bioRxiv2024

Planarians Develop Radiotolerance to Recurrent Ionizing Radiation Exposure

Exposure to ionizing radiation can induce DNA fragmentation, leading to double-strand breaks, the most toxic form of DNA damage. Some organisms have developed mechanisms to overcome the adverse effects of ionizing radiation by enhancing DNA protection and repair. However, the underlying mechanisms driving radiation resistance to maintain genomic integrity and function remain poorly understood. Here, we provide evidence for the development of radiotolerance in the flatworm planarian Schmidtea mediterranea. We implemented a strategy to select animals capable of overcoming repeated rounds of ionizing radiation exposure. We demonstrate that planarians initially exposed to higher amounts of sub-lethal radiation can adapt, gaining the ability to recover reproductive capabilities faster than animals initially exposed to lower amounts of sub-lethal radiation. Our findings show that DNA integrity is reestablished in about one week after five cycles of sub-lethal ionizing radiation exposure. Planarian stem cells, known as neoblasts, can repair repeated DNA double-strand breaks by activating Rad51-mediated homologous recombination. The expression of the neoblast marker smedpiwi-1 and the mitotic activity reach levels similar to unirradiated animals between two and three weeks post-radiation. We describe that planarians develop radiotolerance through recurrent ionizing radiation exposure over several years and survive without apparent functional or morphological defects for an undetermined time.

developmental biology↗

bioRxiv2023

Epigenomic Analyses Identify FOXM1 As a Key Regulator of Anti-Tumor Immune Response in Esophageal Adenocarcinoma

Unlike most cancer types, the incidence of esophageal adenocarcinoma (EAC) has rapidly escalated in the western world over recent decades. Using whole genome bisulfite sequencing (WGBS), we identify the transcription factor (TF) FOXM1 as an important epigenetic regulator of EAC. FOXM1 plays a critical role in cellular proliferation and tumor growth in EAC patient-derived organoids and cell line models. We identify ERBB2 as an upstream regulator of the expression and transcriptional activity of FOXM1. Unexpectedly, Gene Set Enrichment Analysis (GSEA) unbiased screen reveals a prominent anti-correlation between FOXM1 and immune response pathways. Indeed, syngeneic mouse models show that FOXM1 inhibits the infiltration of CD8+ T cells into the tumor microenvironment. Consistently, FOXM1 suppresses CD8+ T cell chemotaxis in vitro and antigen-dependent CD8+ T cell killing. This study characterizes FOXM1 as a significant EAC-promoting TF and elucidates its novel function in regulating anti-tumor immune response.

cancer biology↗

bioRxiv2022

Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation

As one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), arising from distinct cells-of-origin. However, distinguishing cell-type-specific molecular features from cancer-specific characteristics has been challenging. Here, we analyze whole-genome bisulfite sequencing (WGBS) data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both the methylation level (depth) and genomic distribution (breadth) of PMDs across tumor samples. We identify subtype-specific PMDs, which are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While the genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie the genomic distribution PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor such as HNF4A can maintain the binding sites that it establishes in normal cells, while being recruited to new binding sites with novel partners such as FOSL1 in cancer. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of the cell-type-specific PMDs and DMRs identified here in esophageal cancer, are actually markers that co-occur in other cancers originating from related cell types. These findings advance our understanding of the DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.

cancer biology↗

bioRxiv2022

A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Adult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload ([~]30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here we show that despite markedly increased cardiac work, classical cardiac hypertrophy markers were absent in TGAC8, total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes and a network of small interstitial non-cardiac myocytes, manifesting increased proliferation markers and compared to WT. Protein synthesis, proteosome activity, autophagy, and Nrf-2, Hsp90, ACC2 protein levels were increased in TGAC8, but LV ATP and phosphocreatine levels in vivo did not differ by genotype. 2,323 transcripts and 2,184 proteins identified in unbiased omics analyses, spanning a wide array of biological processes and molecular functions in numerous cellular compartments differed in TGAC8 vs WT; and over 250 canonical signaling pathways characteristic of adaptive survival circuitry of cancers, including PI3K and growth factor signaling, cytokine and T cell receptor signaling, immune responses, ROS scavenging, proliferation, protection from apoptosis, and nutrient sensing, were activated in TGAC8; and compared to WT there was a shift from fatty acid oxidation to increased aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, the adaptive paradigm, that becomes activated in the LV of TGAC8 in response to severe chronic, intense AC/PKA/Ca2+ signaling embodies many hallmarks of cancer.

physiology↗

bioRxiv2022

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Inactivation of the tumor suppressor genes TP53 and CDKN2A occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, due to a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have been incompletely characterized. Here we report the development of the first wild-type primary human GEJ organoid model, as well as a CRISPR-edited transformed GEJ organoid model. CRISPR/Cas9 engineering to inactivate TP53 and CDKN2A (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia as well as pro-neoplastic features in vitro and tumor formation in vivo. Notably, lipidomic profiling identified several Platelet-Activating Factors (PTAFs) among the most upregulated lipids in CRISPR-edited organoids; and importantly, PTAF/PTAFR abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) significantly blocked proliferation and other pro-neoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts derived from Eso26, an established esophageal adenocarcinoma (EAC) cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly Forkhead Box M1 (FOXM1). Importantly, FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. In summary, we established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and discovered a potential cancer-therapeutic strategy, while providing insights into pro-neoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia. One Sentence SummaryNovel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/491356v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@18dcb8dorg.highwire.dtl.DTLVardef@2ec0d6org.highwire.dtl.DTLVardef@17622b8org.highwire.dtl.DTLVardef@e184bc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Restoration of DNA Integrity and Cell Cycle by Electric Stimulation in Planarian Tissues Damaged by Ionizing Radiation

Exposure to high levels of ionizing {gamma}-radiation leads to irreversible DNA damage and cell death. Here, we establish that exogenous application of electric stimulation enables cellular plasticity to reestablish stem cell activity in tissues damaged by ionizing radiation. We show that sub-threshold direct current stimulation (DCS) rapidly restores pluripotent stem cell populations previously eliminated by lethally {gamma}-irradiated tissues of the planarian flatworm Schmidtea mediterranea. Our findings reveal that DCS enhances DNA repair, transcriptional activity, and cell cycle entry in post-mitotic cells. These responses involve rapid increases in cytosolic [Ca2+] through the activation of L-type Cav channels and intracellular Ca2+ stores leading to the activation of immediate early genes and ectopic expression of stem cell markers in postmitotic cells. Overall, we show the potential of electric current stimulation to reverse damaging effects of high dose {gamma}-radiation in adult tissues. Furthermore, our results provide mechanistic insights describing how electric stimulation effectively translates into molecular responses capable of regulating fundamental cellular functions without the need for genetic or pharmacological intervention.

developmental biology↗

bioRxiv2020

Epithelial infection with Candida albicans elicits a multi-system response in planarians

Candida albicans is one of the most common fungal pathogens of humans. Prior work introduced the planarian Schmidtea mediterranea as a new model system to study the host response to fungal infection at the organismal level. In the current study, we analyzed host-pathogen changes that occurred in situ during early infection with C. albicans. We found that the transcription factor Bcr1 and its downstream adhesin Als3 are required for C. albicans to adhere to and colonize the planarian epithelial surface, and that adherence of C. albicans triggers a multi-system host response that is mediated by the Dectin signaling pathway. This infection response is characterized by two peaks of stem cell divisions and transcriptional changes in differentiated tissues including the nervous and the excretory systems. This response bears some resemblance to a wound-like response to physical injury; however, it takes place without visible tissue damage and it engages a distinct set of progenitor cells. Overall, we identified two C. albicans proteins that mediate epithelial infection of planarians and a comprehensive host response facilitated by diverse tissues to effectively clear the infection.

developmental biology↗