Wijetunga, N. A. | bioRxiv Science

bioRxiv2025

Autocrine CXCL1-CXCR2 Signaling Mediates Leptomeningeal Resistance to Radiation Therapy

Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer. Proton craniospinal irradiation (pCSI) has emerged as a promising life-prolonging intervention for LM patients, but the response to this treatment varies. Here, we aimed to characterize the molecular basis of pCSI resistance and response. Proteomic analysis of CSF collected from LM patients at baseline (before pCSI), and at multiple time points post-treatment, identified the CXC-motif chemokine, CXCL1, as associated with LM growth. Higher CXCL1 levels in the CSF prior to pCSI correlated with worse response to this treatment. To define the role of CXCL1 in LM, we established syngeneic mouse models of LM-CSI. We found that both metastatic cancer and host cells generate CXCL1. Genetic interruption of Cxcl1 expression in metastatic cancer, but not host cells, impaired cancer cell growth within the leptomeninges. Moreover, a subset of LM cancer cells expressed Cxcr2, the primary receptor for Cxcl1, and this population was enriched over time in the leptomeninges. Transcriptomic profiling of this rare population revealed an enrichment in pathways implicated in cell cycle progression. Finally, interruption of Cxcl1-Cxcr2 signaling with intrathecally-delivered Cxcr2 antagonist hampered LM growth and sensitized the cells to CSI. Our results demonstrate that the Cxcl1-Cxcr2 signaling axis mediates LM growth, and identifies a potential actionable intervention to improve response to pCSI and halt LM progression. One Sentence SummaryCXCL1-CXCR2 axis is a potential actionable therapeutic target to halt leptomeningeal metastasis progression and enhance response to craniospinal irradiation.

cancer biology↗

bioRxiv2017

Intragenomic Redistribution Of Host Transcription Factor Binding With Toxoplasma gondii Infection

The intracellular pathogen Toxoplasma gondii modifies a number of host cell processes. The mechanisms by which T. gondii alters host gene expression are incompletely understood. This study focuses on how the regulators of gene expression in human host cells respond to T. gondii 24 hours following infection to cause specific patterns of transcriptional dysregulation. The most striking finding was the altered landscape of transposase-accessible chromatin by infection. We found both gains and losses of loci of open chromatin enriched in proximity to transcriptionally altered genes. Both DNA sequence motif analysis at the loci changing chromatin accessibility and network analysis of the genes with transcription and regulatory changes implicate a central role for the AP-1 transcription factor. We validated the redistribution of AP-1 in the host genome using chromatin immunoprecipitation studies of the c-Fos component of AP-1. As infection with T. gondii is associated with the cell failing to progress through the cell cycle, all of the changes observed occur in the absence of cell division and within 24 hours, an insight into the dynamism of these transcriptional regulatory events. We conclude that T. gondii infection influences transcriptional regulation through transcription factor re-targeting to modify the cis-regulatory landscape of the host nucleus.\n\nAUTHOR SUMMARYThe complex interactions between the intracellular pathogen Toxoplasma gondii and the host cell manifest as expression changes of host genes. T. gondiis secreted effectors have been extensively studied and include factors that influence the properties of transcription factors, resulting in post-translational modifications and changes in intracellular localization. To gain insights into how T. gondii exerts specific influences on host transcriptional regulation, we used genome-wide approaches to study gene expression, cytosine modifications, and chromatin structure of the host cell 24 hours after infection. The greatest insights were gained from the mapping of loci of transposase-accessible chromatin, revealing a consistently altered pattern of a subset of loci becoming inaccessible, with the simultaneous acquisition of a new set of infection-associated loci of open chromatin. The sequences at these loci were enriched for certain transcription factor binding motifs, in particular that of AP-1, the transcription factor formed by c-Jun and c-Fos heterodimers. Network analysis revealed a central role for c-Jun and c-Fos in the infection-associated perturbations, prompting a chromatin immunoprecipitation approach that confirmed the redistribution of c-Fos in infected cells. We conclude that a T. gondii infection leads to an intragenomic redistribution of host transcription factor binding, with resulting effects on host gene expression.

genomics↗