Biology subjects

Hasani, M.

Publications and source records attributed to Hasani, M..

5 recordsLinked to original sources

bioRxiv2026

Pancreatic progenitor cells respond to laminar shear stress with transcriptomic changes, accompanied by reduced YAP1 activity

The human pancreas secretes digestive fluid that flows through an extensive ductal network before emptying into the duodenum. However, little is known about how hydrodynamic forces influence pancreatic function and development. We hypothesized that pancreatic cells respond to physiological levels of fluid shear stress. In this study, we developed a microfluidic system featuring reversible sealing between the device layer and the cell culture substrate, enabling (1) conventional open-well cell culture prior to fluid shear stress application and (2) selective patterning of proteins and cells for migration studies. Channel dimensions were chosen to support 24-hour perfusion using standard syringe pumps. Using this platform, we investigated effects of physiological shear stress levels representing basal and activated pancreatic function (2, 8 and 33 mPa) on human iPSC-derived pancreatic progenitor cells. Pancreatic progenitor cells exhibit graded sensitivity to shear stress at the transcriptomic level. Specifically, shear stress upregulated expression of cell cycle-related gene sets; endocrine-associated genes including NEUROG3; and Notch receptor ligands (DLL1, DLL3) in a magnitude-dependent manner. The exposure to unidirectional fluid flow also resulted in a reduction in YAP1 protein content, decreased WWTR1 gene expression, and downregulation of YAP/TAZ target genes. Furthermore, barrier-based migration assays under shear stress revealed that cell patches expanded their boundaries both along and against the flow, with greater distance in the direction of flow. Our system and findings may help lay the foundation for understanding biophysical regulation of developmental processes in a physiologically important, yet hard-to-access, epithelial model system.

bioengineering↗

bioRxiv2026

CMTM6-Silencing Microbial Immunotherapy Reprograms PDAC Tumors and Restores T-cell Function

Despite recent advances in immunotherapy for advanced malignancies, Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to current immunotherapy due to dense fibrosis, limited antigen presentation, and myeloid-driven immune suppression. Here we report the tumor-targeting, immune remodeling, and safety profiles of the attenuated Salmonella enterica serovar Typhimurium strain CRC2631, and of iSTORM, a next-generation derivative engineered for tumor-localized CMTM6 silencing. CRC2631 preferentially colonizes orthotopic and genetically engineered PDAC tumors, with enrichment in primary lesions and metastases. Tumor-localized CRC2631 induces chemokine and adhesion programs consistent with leukocyte recruitment, increases intratumoral activated T-cell fractions, and triggers transcriptional signatures aligned with innate sensing, interferon signaling, antigen-processing and presentation, and apoptosis programs. iSTORM extends this platform by delivering CMTM6-targeting shRNA to modulate a PD-L1-stabilizing, myeloid-associated immune-evasion programs within tumor-colonized tissue. Compared with CRC2631, iSTORM increases intratumoral CD8+ T cells, shifts T-cell state toward activation with reduced exhaustion-prone features, strengthens antigen-presentation programs, and achieves deeper tumor control. A lyophilized formulation preserves immune remodeling while improving deployability. Mechanistically, glycan arrays and functional studies support mannose-rich glycan-guided tumor engagement. iSTORM toxicity studies, including systemic cytokine, hematologic, blood chemistry, and lethality demonstrate a favorable safety profile. Collectively, these findings establish iSTORM as a safe, programmable, CMTM6-silencing microbial immunotherapy platform that selectively targets and penetrate PDAC tumors to unleash anti-tumor immune activities. What is already known on this topicPDAC is highly resistant to immune checkpoint blockade because dense stroma and myeloid-dominated suppression prevent effective T-cell infiltration; attenuated Salmonella strains can selectively colonize tumors but first-generation agents showed limited efficacy and safety concerns. What this study addsThis study defines CRC2631/iSTORM as a tumor-selective microbial immunotherapy that exploits surface-exposed, mannose-rich N-glycans to colonize PDAC, delivers CMTM6 silencing, and restores CD8+ T-cell activation and tumor control in models resistant to PD-1 blockade immunotherapy. How this study might affect research, practice or policyThese findings provide a mechanistic blueprint for glycan-guided, CMTM6-targeted bacterial "living drugs," support rational combination strategies for deepening therapeutic effect, and establish a lyophilized, biocontained platform that could be developed into scalable microbial immunotherapies for PDAC and other immunologically cold solid tumors.

cancer biology↗

bioRxiv2025

Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage Transformation

Aberrant activation of the androgen receptor (AR) pathway drives prostate cancer (PCa). Androgen deprivation therapy (ADT) and next-generation AR blockade (e.g., enzalutamide) are initially effective, but virtually all patients develop castration-resistant prostate cancer (CRPC), which frequently transitions to treatment-emergent neuroendocrine PCa (tNEPC) following AR suppression. The molecular logic that links AR blockade to lineage plasticity remains incompletely understood. Here, we identify PSMA2 (Proteasome Subunit Alpha 2) as a treatment-induced effector that mechanistically connects AR blockade to tNEPC evolution. Enzalutamide induces PSMA2 expression in AR-expressing PCa cells. Enforced PSMA2 expression accelerates HSP90 turnover, hypersensitizes AR to residual post-castration androgen, drives AR nuclear activity under androgen-poor conditions, and confers enzalutamide resistance. Conversely, PSMA2 silencing stabilizes HSP90, desensitizes CRPC to androgen, and re-sensitizes resistant cells to enzalutamide-induced cell death. Importantly, PSMA2 also promotes lineage plasticity: treatment-induced PSMA2 enhances transcriptional and phenotypic conversion toward tNEPC. Thus, we uncover a single stress-induced node (PSMA2) that both maintains AR-dependent survival under ADT and fuels the neuroendocrine transition. PSMA2 marks an AR-hypersensitized transitional state and is itself a therapeutically actionable driver of tNEPC evolution, revealing an opportunity for rational interception of the lethal ADT-CRPC-tNEPC trajectory.

cancer biology↗

bioRxiv2024

Controlled Protein-Membrane Interactions Regulate Self-Organization of Min Protein Patterns

Self-organizing protein patterns play an essential role in life, governing important cellular processes, such as polarization and division. While the field of protein self-organization has reached a point where basic pattern-forming mechanisms can be reconstituted in vitro using purified proteins, understanding how cells can dynamically switch and modulate these patterns, especially when transiently needed, remains an interesting frontier. Here, we demonstrate the efficient regulation of self-organizing protein patterns through modulation of simple biophysical membrane parameters. Our investigation focusses on the impact of membrane affinity changes on Min protein patterns at lipid membranes composed of E. coli lipids or minimal lipid composition and we present three major results. First, we observed the emergence of a diverse array of pattern phenotypes, ranging from waves to snowflake-like structures. Second, we establish the dependency of these patterns on the density of protein-membrane linkers. Finally, we demonstrate the fine-tuning of snow-flake-like patterns by regulating membrane charge through lipid composition. Our results demonstrate the significant influence of membrane linkage as a straightforward biophysical parameter governing protein pattern formation. Our research points towards a simple yet intriguing mechanism by which cells can adeptly tune and switch protein patterns on the mesoscale.

biophysics↗

bioRxiv2023

Resin acids play key roles in shaping microbial communities during degradation of spruce bark

The bark is the outermost defense of trees against microbial attack, largely thanks to toxicity and prevalence of extractive compounds. Nevertheless, bark decomposes in nature, though by which species and mechanisms remains unknown. Here, we have followed the development of microbial enrichments growing on spruce bark over six months, by monitoring both chemical changes in the material and performing community and metagenomic analyses. Carbohydrate metabolism was unexpectedly limited, and instead a key activity was metabolism of extractives. Resin acid degradation was principally linked to community diversification with specific bacteria revealed to dominate the process. Metagenome-guided isolation facilitated the recovery of the dominant enrichment strain in pure culture, which represents a new species (Pseudomonas abieticivorans sp. nov.), that can grow on resin acids as a sole carbon source. Our results illuminate key stages in degradation of an abundant renewable resource, and how defensive extractive compounds have major roles in shaping microbiomes.

microbiology↗