Biology subjects

Rosenbaum, S. R.

Publications and source records attributed to Rosenbaum, S. R..

4 recordsLinked to original sources

bioRxiv2026

Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit

Rhabdomyosarcoma (RMS) is a multi-subtype, high-risk pediatric sarcoma with a low mutational burden. The mutations found in RMS often alter genes involved in transcriptional control. Approaches to target dysregulated RMS transcription have remained elusive. Here, we develop a novel approach to target RMS transcription comprising simultaneous targeting of two distinctly acting transcriptional co-activators. We discover a common identity-controlling pan-RMS core regulatory circuit (CRC) composed of oncogenic and lineage-specific myogenic master transcription factors (mTFs). Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent inhibitor of the pan-RMS CRC, though with efficacy-limiting toxicities. To enhance efficacy, we identify the mTF-binding co-activator EYA2 as a co-factor of this pan-RMS CRC and exploit a new second-generation EYA1/2 inhibitor, LG1-34, to disrupt its function. Combined co-activator inhibition inactivates the CRC and synergistically reduces RMS growth. This strategy dually targets CRC-associated co-activators to cooperatively suppress the RMS transcriptome and enforce cell death.

cancer biology↗

bioRxiv2026

Genetic and Pharmacologic Targeting of Eya3 in Macrophages Drives Anti-Tumor Immunity in Triple-Negative Breast Cancer

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that remains difficult to treat despite its relatively high immunogenicity, as tumors frequently evade immune destruction through poorly understood mechanisms. Here, we discover a previously unrecognized role for Eya3 within macrophages in the tumor immune microenvironment, where its expression is elevated. Using macrophage Eya3 knockdown and conditional knockout models, we show that Eya3 depletion induces coordinated transcriptional and functional changes in macrophages, enhancing migration, antigen processing, and inflammatory signaling associated with anti-tumor immunity. Strikingly, macrophage-targeted deletion of Eya3 reprograms the immune response in TNBC, increasing CD8+ T cell infiltration, suppressing primary tumor growth, and prolonging survival. Pharmacologic inhibition of Eya3 tyrosine phosphatase activity with a novel allosteric inhibitor, LG1-34, mirrors this effect, dramatically reducing primary TNBC growth through immune-mediated mechanisms that likely act both though targeting tumor and immune cells. These findings identify Eya3 as a macrophage-intrinsic checkpoint on anti-tumor immunity, identifying a new potential vulnerability in TNBC. Significance StatementTargeting Eya3 tyrosine phosphatase activity in tumor-associated macrophages reprograms the TNBC immune microenvironment and restores anti-tumor immunity, identifying a new potential therapeutic vulnerability in a cancer that has limited treatment targeted options.

cancer biology↗

bioRxiv2024

An EYA3/NF-κB/CCL2 signaling axis suppresses cytotoxic NK cells in the pre-metastatic niche to promote triple negative breast cancer metastasis

Patients with Triple Negative Breast Cancer (TNBC) exhibit high rates of metastases and poor prognoses. The Eyes absent (EYA) family of proteins are developmental transcriptional cofactors/phosphatases that are re-expressed and/or upregulated in numerous cancers. Herein, we demonstrate that EYA3 correlates with decreased survival in breast cancer, and that it strongly, and specifically, regulates metastasis via a novel mechanism that involves NF-kB signaling and an altered innate immune profile at the pre-metastatic niche (PMN). Remarkably, restoration of NF-kB signaling downstream of Eya3 knockdown (KD) restores metastasis without restoring primary tumor growth, isolating EYA3/NF-kB effects to the metastatic site. We show that secreted CCL2, regulated downstream of EYA3/NF-kB, specifically decreases cytotoxic NK cells in the PMN and that re-expression of Ccl2 in Eya3-KD cells is sufficient to rescue activation/levels of cytotoxic NK cells in vitro and at the PMN, where EYA3-mediated decreases in cytotoxic NK cells are required for metastatic outgrowth. Importantly, analysis of public breast cancer datasets uncovers a significant correlation of EYA3 with NF-kB/CCL2, underscoring the relevance of EYA3/NF-kB/CCL2 to human disease. Our findings suggest that inhibition of EYA3 could be a powerful means to re-activate the innate immune response at the PMN, inhibiting TNBC metastasis. SignificanceEYA3 promotes metastasis of TNBC cells by promoting NF-kB-mediated CCL2 expression and inhibiting cytotoxic NK cells at the pre-metastatic niche, highlighting a potential therapeutic target in this subset of breast cancer.

cancer biology↗

bioRxiv2017

Long-term consolidation switches goal proximity coding from hippocampus to retrosplenial cortex

Recent research indicates the hippocampus may code the distance to the goal during navigation of newly learned environments. It is unclear however, whether this also pertains to highly familiar environments where extensive systems-level consolidation is thought to have transformed mnemonic representations. Here we recorded fMRI while University College London and Imperial College London students navigated virtual simulations of their own familiar campus (> 2 years of exposure) and the other campus learned days before scanning. Posterior hippocampal activity tracked the proximity to the goal in the newly learned campus, but not in the familiar campus. By contrast retrosplenial cortex tracked the distance to the goal in the familiar campus, but not in the recently learned campus. These responses were abolished when participants were guided to their goal by external cues. These results open new avenues of research on navigation and consolidation of spatial information and help advance models of how neural circuits support navigation in novel and highly familiar environments.\n\nSignificance StatementHistorically, research on the hippocampal formation has focused on its role in long-term memory and navigation - often in isolation. No study to date has directly compared realistic navigation within familiar with recently learned environments, nor has it been explored how the neural substrates, along with computational codes, may change. In this study, we show for the first time, a shift from hippocampal to cortical coding of distance to a goal during active navigation. This study bridges the gap between memory consolidation and navigation, and paves the way for more functional and realistic understanding of the hippocampus.

neuroscience↗