Biology subjects

Amirfallah, A.

Publications and source records attributed to Amirfallah, A..

3 recordsLinked to original sources

bioRxiv2026

PSGL-1 blockade delays relapse to BRAF/MEK inhibition in cutaneous melanoma

Advanced BRAF-mutant cutaneous melanoma can be treated with targeted therapy when immune checkpoint inhibitors (ICIs) fail or are not a feasible option. Nevertheless, most patients do not achieve a durable response, highlighting the critical need for therapeutic partners that enhance the long-term efficacy of targeted therapy. Transcriptomic analysis of a BRAF-mutant melanoma model of acquired resistance identified P-selectin glycoprotein ligand-1 (PSGL-1) as a top-upregulated immune mediator upon resistance acquisition. PSGL-1 is a key regulator of CD8+ T cell exhaustion and differentiation, and its inhibition has been shown to enhance T cell function across multiple disease models. Based on these observations, we hypothesized that combined targeting of BRAF/MEK and PSGL-1 would improve anti-tumor responses. Here, we demonstrate that dual inhibition of BRAF/MEK and PSGL-1 elicits durable tumor control in a preclinical model of PD-1-refractory cutaneous melanoma. Single-cell RNA sequencing of the tumor microenvironment reveals robust reprogramming of intratumoral CD8+ T cells toward a less terminally differentiated, memory-like phenotype following combined BRAF/MEK and PSGL-1 targeting. Consistent with these findings, CD8+ T cells in the tumor-draining lymph nodes of PSGL-1-/- mice exhibit enhanced functionality and a less differentiated state of exhaustion when compared with wild-type mice. To extend these observations to a translationally relevant setting, we further show that antibody-mediated blockade of PSGL-1, in combination with BRAF/MEK inhibition, yields superior anti-tumor activity compared with either monotherapy. Collectively, these findings identify PSGL-1 as a promising therapeutic target to enhance the durability of targeted therapy and provide a strong rationale for future clinical evaluation.

immunology↗

bioRxiv2026

It's Not Rewarding for Mitochondria: Dopamine-Induced Mitochondrial Dysfunction Activates cGAS-STING to Drive IL-6 Secretion in Macrophages

Despite increasing data demonstrating dopamine as an inflammatory mediator of the innate immune system, the molecular mechanisms underlying its effects in human cells remain incompletely defined. Here, we define an unrecognized pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism, in a time-dependent manner. These events promote the mtDNA release into the cytoplasm, triggering cGAS-STING pathway and downstream NF-{kappa}B signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. Together, these findings redefine the interface between dopamine signaling and systemic inflammation and highlight an unrecognized source of inter-individual variation in immune responses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/719926v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@e2c133org.highwire.dtl.DTLVardef@fa0a15org.highwire.dtl.DTLVardef@1ac1f91org.highwire.dtl.DTLVardef@14c8c53_HPS_FORMAT_FIGEXP M_FIG C_FIG Dopamine induces mitochondrial dysfunction mediated through dopamine receptors signaling. This includes alterations in mitochondrial membrane potential, leading to excessive DRP1-mediated mitochondrial fission, increased production of mitochondrial superoxide, and metabolic reprogramming toward enhanced glycolysis with reduced oxidative phosphorylation. Sustained mitochondrial damage is further exacerbated by impaired mitophagy, resulting in the release of mitochondrial DNA (mtDNA) into the cytoplasm. Cytosolic mtDNA, acting as a double-stranded DNA ligand, activates the cGAS-STING pathway, which subsequently induces NF-{kappa}B signaling, ultimately driving the production and secretion of the pro-inflammatory cytokine IL-6. Created on Biorender.com.

immunology↗

bioRxiv2025

Shared molecular consequences of epigenetic machinery disruption in neuronal progenitors

The Mendelian disorders of the epigenetic machinery (MDEMs) are an emerging cause of intellectual disability and growth abnormalities, which commonly disrupt hippocampal function. To investigate consequences of epigenetic machinery (EM) disruption during neurodevelopment, we systematically knocked out (KO) EM factors in neuronal progenitors isolated from the murine hippocampus and established a neurodifferentiation model to interrogate their functions. We then profiled gene expression and DNA methylation (DNAm) in the EM-KOs using RNA sequencing and Nanopore long-read DNA sequencing. While Dnmt1-KO induced extensive DNAm alterations, Kmt2a-KO had little effect on methylation. Nevertheless, the disruption of Kmt2a and Dnmt1 produced strikingly convergent transcriptional changes. Loss of either EM factor led to premature neuronal differentiation, partially explaining this convergence, and MYC appeared as a shared regulatory node linked to downregulation of cell-cycle programs in these cells. Extending our methylation analysis to 46 EM genes, we found that loss of DNA methyltransferases induced the strongest DNAm changes, whereas other EM-KOs had subtle or negligible effects. However, clustering of EM-KOs based on promoter DNAm levels revealed three distinct EM subgroups, of which two were enriched for interactions with the DNAm machinery. Allele-specific analysis of DNAm further identified a single differentially methylated region shared across the 46 EM-KOs, localized to the FVB allele over the Zic4 3UTR. Furthermore, Zic4 overexpression appears to maintain the neuronal progenitor state, suggesting functional relevance of this locus. Taken together, our results reveal both gene-specific and convergent effects across diverse EM-KOs and provide new insight into the molecular etiology of the MDEMs.

genomics↗