Wiechert, A. | Search bioRxiv

bioRxiv2025

Epitranscriptomic landscape of vascular smooth muscle cell phenotypic transitions highlights uridine RNA modifications associated with post-transcriptional regulation

BackgroundVascular smooth muscle cells (VSMCs) phenotypic plasticity can modulate atherosclerosis progression. Although several gene regulatory steps towards pro-inflammatory phenotypes have been well-studied, epitranscriptomic changes during this transition and their regulatory roles remain unexplored. Methods and ResultsPrimary human VSMCs stimulated with TGF-{beta}1 to induce atheroprotective, contractile, and matrix-producing state and with IL1-{beta} plus PDGF-BB to induce a highly energetic, pro-inflammatory state, confirmed by Illumina bulk RNA sequencing and proteomics. Untargeted screening of mRNA base modifications using Oxford Nanopore Technologies direct RNA sequencing and xPore analysis revealed enhanced uridine modification within a GUUUU motif in pro-inflammatory VSMCs. Modified uridines were enriched in 3-UTR and accessible RNA structures, with implications on Poly(A) tail dynamics and miRNA binding. ConclusionsAtheroprotective and pro-atherogenic treatments induce distinct epitranscriptomic landscapes composed of different modification types, often co-localized in the transcript. Modified uridines in mRNAs are abundant in a high-energy, pro-inflammatory VSMC state and associated with post-transcriptional regulation. n summary, epitranscriptomics adds a novel regulatory layer to VSMC phenotypic transitions critical for atherosclerosis development and progression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/694735v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@933071org.highwire.dtl.DTLVardef@151564borg.highwire.dtl.DTLVardef@f862e9org.highwire.dtl.DTLVardef@125c509_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG

molecular biology↗

bioRxiv2017

CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors

Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, however these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via LCK signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance via a bifurcating signaling axis and provide an opportunity to target both signaling pathways in endometrioid tumors.\n\nSUMMARYCD55 is a membrane complement regulatory protein that attenuates complement-mediated cytotoxicity. Saygin et al. elucidate a new role for CD55 as a signaling hub for cancer stem cell self-renewal and cisplatin resistance pathways in endometrioid tumors and open a new line of research into chemotherapeutic-refractory cancers.\n\nAbbreviations

cancer biology↗