Biology subjects

Hornstein, N.

Publications and source records attributed to Hornstein, N..

3 recordsLinked to original sources

bioRxiv2026

The Y chromosome gene KDM5D restrains CD8+ T cell antitumor immunity through TCR and cholesterol-exhaustion programs

Sex differences in immunity shape cancer risk, autoimmunity, and responses to immunotherapy, yet the sex-chromosome genes that regulate antitumor T cell function remain incompletely defined. Here, we identify the Y chromosome-encoded KDM5D histone demethylase as a male-specific suppressor of CD8+ T cell antitumor immunity. In murine colorectal cancer (CRC) models, male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCR{beta} abundance, and proximal TCR signaling relative to female CD8+ T cells. CRISPR-RNP-mediated KDM5D depletion in male CD8+ T cells enhanced effector function, increased TCR{beta} expression, augmented TCR signaling, and improved tumor control after adoptive transfer. Transcriptomic and functional analyses further linked KDM5D to cholesterol biosynthesis and exhaustion-associated programs, with KDM5D depletion reducing SREBP2/XBP1-associated cholesterol and exhaustion signatures. Correspondingly, human CRC single-cell analyses supported the clinical relevance of this axis, showing enrichment of exhausted and cholesterol-associated CD8+ T cell states in male tumors. Pharmacologic inhibition of cholesterol biosynthesis with lovastatin partially attenuated select exhaustion-associated markers in male CD8+ T cells and delayed tumor growth in vivo. Together, these findings define KDM5D as a sex chromosome-encoded regulator of male CD8+ T cell dysfunction and point to cholesterol-exhaustion programs as a potential therapeutic vulnerability in male CRC.

cancer biology↗

bioRxiv2026

KRAS inhibition is an effective therapy for appendiceal adenocarcinoma

BackgroundAppendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear. MethodsWe evaluated KRASG12D-specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRASmut organoid and orthotopic PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. Clinical outcomes were also assessed in six heavily pre-treated AA patients treated with KRAS inhibitors. ResultsMRTX1133 was highly effective for KRASG12D organoids (IC50=4.1 nM); both KRASG12D and KRASG12V organoids were sensitive to RMC-6236 (IC50=4.4 nM vs 0.5 nM, respectively). In orthotopic PDX models of peritoneal carcinomatosis from AA, MRTX1133 significantly reduced tumor growth in the KRASG12D model TM00351, and RMC-6236 reduced tumor growth in KRASG12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Sets Enrichment Analysis (GSEA) revealed significant downregulations of E2F targets (NES=-1.9, p-adj=0.06) and the newly developed RAS/ERK (NES=-2.3, p-adj=0.06) gene set, consistent with the observed decrease in cell proliferation. There was marked upregulation of EMT (NES=2.7, FDR<0.001) and TGF-{beta} signaling (NES=2.3, FDR=0.004) in remaining tumor cells, suggesting these pathways could confer resistance. scRNA-seq analysis of TME showed dramatic shifts in cancer-associated fibroblasts (CAFs), with KRAS inhibition driving a shift from normal fibroblasts to inflammatory CAFs, and upregulation of interferon alpha and gamma pathways, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. In a cohort of 6 heavily pre-treated patients with AA treated with KRAS inhibitors (1 G12D, 3 G12C, 2 pan-KRAS), all had biochemical response based on CEA/Ca19-9 or ctDNA and clinical benefit by RECIST criteria (1 CR, 1 PR, 4 SD). ConclusionsWhile effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of EMT and TGF-{beta} pathways may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

cancer biology↗

bioRxiv2018

Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knock-Out Mice

FMRP is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in Fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene-specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we used ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24 day-old Fmr1 knock-out mice. We found a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP, and an increase for terminal oligo-pyrimidine (TOP) motif-containing genes canonically controlled by mTOR-4EBP-eIF4E signaling. Amino acid motif- and gene-level analyses both showed a widespread reduction of translational pausing in Fmr1 knock-out mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in Fragile X syndrome.

molecular biology↗