Sunday, May 18, 2025
5/18/2025
Inflammatory Signaling in the Leptomeninges - PROJECT SUMMARY Leptomeningeal metastasis (LM) or spread of tumors into the spinal fluid-filled spaces that surround the brain and spinal cord represents an increasingly common, lethal complication of malignancy. A hallmark of LM is the robust inflammation that accompanies cancer cell growth in this space. Despite this inflammatory response to tumor, cancer cells invariably grow and overtake this space. We hypothesize that cancer within the leptomeningeal space derives benefit from this inflammatory signaling. Leveraging a collection of clinical samples obtained during the course of radiation treatment, we find that levels of CXCL1 increase in the spinal fluid in the setting of leptomeningeal metastasis, drop following radiation therapy, and return in concert with cancer cell growth in the space. In this proposal, we will investigate the relationship between leptomeningeal cancer cell growth and leptomeningeal-generated CXCL1. We have established immune-competent mouse models of LM, as well as craniospinal treatment techniques that faithfully replicate human disease and its treatment. We will leverage these mouse models to mechanistically dissect the CXCL1-CXCR2 signaling axis within the leptomeningeal space by first identifying cancer cell signals that provoke leptomeningeal CXCL1 generation. We will demonstrate the source of CXCL1, though single cell RNA sequencing, immunofluorescence, biochemical fractionation, in vitro coculture systems and immune-competent mouse models. To characterize and interrupt cancer cell responses to LM-generated cytokines, we will capture CXCR2 expression and downstream signaling in leptomeningeal cancer cell populations within leptomeningeal and extracranial microenvironments through flow cytometry and scRNASeq, interrupting the CXCR2-CXCL1 axis through CXCR2 blocking antibodies, inhibitors, and CRISPRi. Our comprehensive approach will capture the molecular call-and-response between cancer cells and the leptomeningeal microenvironment, focusing on the inflammatory signaling co- opted by cancer cells to support their own growth. Our unparalleled collection of human samples, facility with molecular interrogation of these samples, and innovative mouse modeling approaches enable thoughtful, mechanistic dissection of clinically-relevant targets against a destructive central nervous system malignancy with limited treatment options.
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