Biology subjects

Wu, S. K.

Publications and source records attributed to Wu, S. K..

4 recordsLinked to original sources

bioRxiv2024

The Senescence-Associated-Secretory Phenotype constituting HIF-1α activation is independent of micronuclei induction and associated cGAS-mediated interferon response

The Senescence-Associated Secretory Phenotype (SASP), characterized by the upregulation of inflammatory cytokines, is triggered during senescence by anti-proliferation stresses, including replicative exhaustion, {gamma}-irradiation, Ras oncogene induction, and centrosome amplification. The elucidation of common signalling pathway(s) activated in SASP, induced by different anti-proliferation stresses, remains an important question. Indeed, micronuclei activation of the cGAS/Sting pathway, which has been thought to drive SASP(Kwon, Leibowitz, and Lee, 2020), remains controversial(Flynn, Koch, and Mitchison, 2021; Sato and Hayashi, 2024; Takaki et al., 2024). In this report, analyses of various cell lines induced to undergo senescence by diverse stressors revealed that HIF-1 is specifically induced in senescence but not in quiescence. Consistent with our previous findings(Wu et al., 2023a), we have further demonstrated how centrosome amplification induces a non-canonical SASP dominated by HIF-1 activation rather than the classical NF{kappa}B signaling. Lastly, we revealed that during SASP, centrosome amplification-generated micronuclei do not activate the cGAS/Sting-mediated interferon response. Together, our findings demonstrate that HIF-1-activation in SASP is a defining feature of the SASP induced by diverse stressors, acting independently of micronuclei generation and cGAS/Sting activation.

cell biology↗

bioRxiv2023

Co-evolution of spheroid fluidization and mechanical fracture in a morphogenic cascade

Cells migrate and invade tissues during development, immune responses, and cancer. Collective invasion is generally understood to be driven by invading cells unjamming and pushing through barriers such as the extracellular matrix and surrounding tissues. Whether these barriers actively contribute to invasion remains unclear. Using ovarian adenocarcinoma spheroids invading mesothelium derived from benign pleural effusions as an experimental model, combined with modelling, we examine invasion across molecular to multicellular scales. We identify intercellular integrin adhesions linking invasive leader cells to the tissue barrier, triggering apical constrictions within the barrier. This constriction shrinks cell-cell contacts, leading to barrier rupture. Thus, the tissue barrier plays a mechanically active role in invasion. Rather than cells pushing through, we find that coordinated subcellular contractility between the invading leader cell and the barrier drives barrier tensile rupture and invasion, independent of a jamming transition. Together, our findings challenge prevailing paradigms of collective cell invasion.

cell biology↗

bioRxiv2020

The Senescence-Associated-Secretory-Phenotype induced by centrosome amplification constitutes a pathway that activates Hypoxia-Inducible-Factor-α.

The Senescence-Associated-Secretory Phenotype (SASP) promote paracrine invasion however may also suppress tumour growth, thus generating complex phenotypic outcomes. Although centrosome amplification can induce proliferation arrest, the subsequent fate of cells with centrosome amplification remains elusive. Here, we report that centrosome amplification induces a variant SASP, constituting a pathway activating paracrine invasion. The centrosome amplification SASP is non-canonical as it lacks detectable DNA damage or prominent NF-{kappa}B activation. Instead, involving Rac activation and reactive oxygen species production. Consequently, inducing hypoxia-inducible factor 1 and associated genes, which includes pro-migratory factors such as ANGPTL4. Since senescent cells also have poor fitness, it is tempting to speculate that centrosome amplification induced SASP is one explanation for why extra centrosomes promote malignancy in some experimental models but are neutral or inhibitory in others.

cell biology↗

bioRxiv2020

RNA matchmaking remodels lncRNA structure and promotes PRC2 activity

Human Polycomb Repressive Complex 2 (PRC2) catalysis of histone H3 lysine 27 methylation at certain loci depends on long noncoding RNAs (lncRNAs). Yet, in apparent contradiction, RNA is a potent catalytic inhibitor of PRC2. Here we show that intermolecular RNA-RNA interactions between the lncRNA HOTAIR and its target genes can relieve RNA inhibition of PRC2. RNA matchmaking is promoted by heterogenous nuclear ribonucleoprotein (hnRNP) B1, which uses multiple protein domains to bind regions of HOTAIR via multi-valent protein-RNA interactions. Chemical probing demonstrates that RNA matchmaking changes HOTAIR RNA structure. Genome-wide HOTAIR/PRC2 activity occurs at genes whose transcripts can make favorable RNA-RNA interactions with HOTAIR. We demonstrate that RNA-RNA matches of HOTAIR with target gene RNAs can relieve the inhibitory effect of a single lncRNA for PRC2 activity. Our work highlights an intrinsic switch that allows PRC2 activity in specific RNA contexts, which could explain how many lncRNAs work with PRC2.

biochemistry↗