Abstract Inside the cell nucleus, nuclear speckles are a predominant type of nuclear body present in the cells throughout our bodies. While first observed by Ramon y Cajal over 100 years ago, speckles have only recently been recognized as a major layer of gene regulation that boosts gene expression by assisting multiple steps of RNA production. Large genomic regions spanning 10s of megabases are consistently organized around speckles, with regulation of chromatin position at speckles occurring at finer scales of ∼10kb-1Mb. Hence, speckles may help direct functional programs within a cell by coordinating expression of large, but specific, groups of genes. In cancer, we found that speckles exist in two major states that correlate strongly with patient outcomes in neuroblastoma and clear cell renal cell carcinoma (ccRCC). These speckle states showed dramatic differences in expression of the speckle-associated gene neighborhoods. Because certain types of genes reside within speckle-associated chromatin, speckle states correlate with broad functional programs such as protein translation and oxidative phosphorylation as well as ccRCC-specific functional programs such as HIF-2alpha-induced angiogenesis and metabolism pathways. Consistent with distinct gene regulatory programs, ccRCC tumors display tumor microenvironment differences, particularly in tumor vasculature, between the two speckle states. While these data indicate that speckles can be used as a multifunctional readout for ccRCC tumor phenotypes, what drives speckle states in ccRCC is unclear. In other efforts in the lab, we combined analysis of public data with experimental approaches to uncover that transcription factors, hormone signaling, and immune signaling globally regulate expression of genes within speckle-associated chromatin. These efforts provide clues as to what may regulate nuclear speckle functions. Ultimately, by understanding the upstream drivers and downstream consequences of speckle states in ccRCC, we hope to advance nuclear speckles as potential therapeutic targets as well as biomarkers capable of stratifying patient risk and informing treatment decisions. Citation Format: Sana Mir, Hiroe Namba, Milena Stepic, Kate Alexander. Nuclear speckles in ccRCC abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr IA025.
Mir et al. (Fri,) studied this question.