Biology subjects

Bae, S. J.

Publications and source records attributed to Bae, S. J..

4 recordsLinked to original sources

bioRxiv2026

Reprogramming VHL with molecular glues enables selective degradation of caspase-2

Molecular glue degraders (MGDs) reprogram E3 ligases to eliminate neosubstrates, yet their application has largely been confined to CRBN. Here, we identify caspase-2 as a new neosubstrate for von Hippel-Lindau (VHL), expanding the scope of VHL-based MGDs. Guided by a focused VHL ligand library design, we employed TurboID-based proximity labeling to discover stereoisomeric compounds (dCASP2-1 and dCASP2-2) that selectively recruit caspase-2 to VHL and promote its ubiquitin-proteasome system-dependent degradation. Further structure-activity relationship (SAR) studies yielded dCASP2-3 and dCASP2-4, which enhanced degradation potency (by 622-fold relative to dCASP2-1) and abolished enantioselectivity. Mechanistic mapping localized the degrader-induced interface to a two-helix region of the caspase-2 CARD domain, with residues H33, P34, and D100 essential for VHL engagement. Degron-guided computational modeling of the VHL/MGD/caspase-2 ternary complex provided structural insight into neosubstrate recognition. Together, we report the development of VHL molecular glues that selectively and potently degrade caspase-2, offering chemical probes to interrogate its functions in apoptosis and stress responses, while broadening the substrate landscape of VHL-based MGDs.

biochemistry↗

bioRxiv2024

Adherent-suspension plasticity promotes the dissemination and colonization of circulating tumor cells

Cell competition within the primary tumor drives tumor growth by promoting the uncontrolled proliferation of winner cells and eliminating loser cells by sensing cell fitness. However, the mechanism of how cell competition confers the loser cells with the metastatic potential of circulating tumor cells (CTCs) to transit between dissemination and colonization remains elusive. Here we found cell competition gives rise to less fit but viable cells that transformed into CTCs via adherent-to-suspension transition (AST) mechanisms. The induction of hematopoietic transcription factors hijacked by solid tumor cells rendered CTCs competent to reprogram their anchorage dependency and disseminate into the bloodstream, while subsequent suppression of these factors was critical to regain adhesion and colonize metastatic lesions. Disrupting the oscillatory dynamics of AST factors blocked the adherent-suspension plasticity (ASP) of breast cancer CTCs and suppressed lung metastasis. Furthermore, multiregional single-cell transcriptomic analyses of matched primary tumors, CTCs, and metastatic lesions from de novo metastatic breast cancer patients demonstrate the critical role of ASP in metastasis. SignificanceWe demonstrate cell competition-mediated displacement of loser cells manifests dynamic oscillation of AST factors that confer anchorage plasticity to circulating tumor cells critical for their dissemination and colonization in metastasis. These findings highlight the potential of targeting AST factors to develop effective anti-metastatic therapies.

cancer biology↗

bioRxiv2024

cGAS deficient mice display premature aging associated with de-repression of LINE1 elements and inflammation

Aging-associated inflammation, or inflammaging" is a driver of multiple age-associated diseases. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS contributes to inflammaging by responding to endogenous signals such as damaged DNA or LINE1 (L1) cDNA which forms in aged cells. While cGAS knockout mice are viable their aging has not been examined. Unexpectedly, we found that cGAS knockout mice exhibit accelerated aging phenotype associated with induction of inflammation. Transcription of L1 elements was increased in both cGAS knockout mice and in cGAS siRNA knockdown cells associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein. Cells from cGAS knockout mice showed increased chromatin accessibility and decreased DNA methylation on L1 transposons. Stimulated emission depletion microscopy (STED) showed that cGAS forms nuclear condensates that co-localize with H3K9me3 heterochromatin marks, and H3K9me3 pattern is disrupted in cGAS knockout cells. Taken together these results suggest a previously undescribed role for cGAS in maintaining heterochromatin on transposable elements. We propose that loss of cGAS leads to loss of chromatin organization, de-repression of transposable elements and induction of inflammation resulting in accelerated aging.

cell biology↗

bioRxiv2019

Associations between absolute neutrophil count and lymphocyte-predominant breast cancer

Tumor-infiltrating lymphocytes (TILs) might be associated with host-cell mediated immunity, which could be partly reflected by peripheral blood cell counts. We aimed to investigate whether peripheral blood cell counts are associated with TILs in breast cancer. Between August 2016 and July 2018, we evaluated the percentage of stromal TILs in breast cancer patients who underwent primary surgery, using the standardized methodology proposed by the international TIL Working Group. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors having high TIL levels ([≥] 50%). Peripheral blood cell counts including absolute neutrophil counts (ANC), absolute lymphocyte counts (ALC) and neutrophil-to-lymphocyte ratio (NLR) was obtained from pretreatment laboratory data. Of the 684 patients, 99 (17.2%) had LPBC, and 478 (82.8%) had non-LBPC. In a comparison of 3 markers of peripheral blood counts, LPBC had a significantly lower mean ANC than non-LPBC (3,330 vs. 3,660; P=0.004), but the other means were not different. Decreasing ANC was an independent clinical factor in predicting LPBC (OR: 0.736, 95% CI: 0.591-0.917; P=0.004). Low peripheral ANC might be linked with LPBC, supporting the hypothesis that systemic immune cell counts might be associated with the tumor-immune microenvironment.

immunology↗