Biology subjects

Lee, C.-F.

Publications and source records attributed to Lee, C.-F..

4 recordsLinked to original sources

bioRxiv2025

Subcellular transcriptome of radial glia reveals compartmentalized control of cortical development

RNA localization and local translation mediate spatial and temporal control of polarized cells, including radial glial cells (RGCs) which produce and organize neurons and glia. Within RGCs, RNAs are transported long distances to basal endfeet, where they can undergo local translation. However, the subcellular composition of RGCs and function of local gene regulation remains largely unknown. Here, we discover that basal endfeet harbor a rich transcriptome including a Dynein component critical for subcellular RGC function. By purifying RGC compartments in vivo, we discover [~]3000 endfoot transcripts, including [~]800 highly enriched compared to cell bodies. Many endfoot-enriched transcripts exhibit conserved subcellular localization in neurons and glia and are associated with neurodevelopmental disease. We show that endfoot-enriched Dync1li2 regulates RGC basal morphology and subsequently interneuron organization. Finally, we develop LOCAL-KD, a CRISPR-Cas13 based method for subcellular mRNA knockdown in vivo. Leveraging this, we demonstrate that endfoot-localized Dync1li2 is critical for RGC morphology. Our study establishes experimental paradigms to understand RNA localization in the nervous system. Moreover, we discover RGCs have a vast subcellular transcriptome, revealing foundational insights into how RGCs control cortical development.

neuroscience↗

bioRxiv2025

Mesophilic compostability of polylactic acid and the associated microbiome as revealed by metagenomics

Polylactic acid (PLA), the most popular bioplastic, has high sustainability potential as it is bio-sourced and also harbors biodegradability. A form of its biodegradability is via composting, and it was previously established that thermophilic temperatures are needed for PLA breakdown in composts. Here we report the development of composts that have overcome the temperature requirement needed for PLA composting. Our mesophilic composts exhibited clear PLA biodegradability, and this is due to specific biological activity enriched in our material. To investigate the nature of this mesophilic activity, we conducted metagenomics analysis to reveal the microbial composition and enzyme-coding potential associated with PLA biodegradation. These efforts revealed multiple enzyme subtypes with strong enrichment on PLA surfaces in our trained composts, and the top candidate was a type of hydro-lyase, an enzyme that can cleave carbon-carbon and carbon-oxygen bonds, both present in the chemical structure of PLA, in the absence of water. Hydro-lyases represent a novel class of enzymes that could facilitate PLA degradation, and our results point to the model that the combinatorial action of multiple types of enzymes is what drives PLA biodegradation and how the temperature barrier for PLA composting is overcome.

microbiology↗

bioRxiv2022

ATR inhibition augments the efficacy of lurbinectedin in small cell lung cancer

Abstract/SummarySmall cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC are particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia-mutated and rad3-related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid and in-vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell-cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which were resistant to first-line therapies displayed decreased CDKN1A/p21 expression and increased ERCC5/XPG indicating they were primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/520783v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@19acf72org.highwire.dtl.DTLVardef@a9703forg.highwire.dtl.DTLVardef@86592org.highwire.dtl.DTLVardef@1448372_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Nuclear morphology and functional characteristics that enable survival of cells in the polyaneuploid cancer cell state following cytotoxic chemotherapy

In this study, we characterized nuclear morphology and function as cancer cells underwent recovery following chemotherapeutic treatment to identify the unique characteristics associated with treatment resistance and successful survival. Cells that survived following treatment and resisted therapy-induced cell death were predominantly mononucleated with increased nuclear/cellular size, enabled by continuous endocycling. We found that cells that survive after therapy release likely employ more efficient DNA damage repair and exhibit a distinct nucleolar phenotype - fewer but larger nucleoli - and increased rRNA levels. These data support a paradigm where soon after therapy release, the treated population mostly contains cells with a high level of widespread and catastrophic DNA damage that leads to apoptosis, while the minority of cells that have successful DDR are more likely to access a pro-survival state. These findings suggest that one way cancer cells can survive systemic therapy is to enter the polyaneuploid cancer cell (PACC) state, a recently-described mechanism of therapy resistance. Cancer cells in this state are physically enlarged, undergo whole-genome doubling resulting in polyaneuploid genomes, and are associated with worse prognosis in cancer patients. The PACC state is accessed when a cancer cell experiences external stress, such as genotoxic chemotherapy; after a period of recovery, cells exit the PACC state and resume proliferation to repopulate the tumor cell pool. Our findings demonstrate the fate of cancer cells following chemotherapy treatment and define key characteristics of the resistant PACC state. This work is essential for understanding and, ultimately, targeting, cancer resistance and recurrence.

cancer biology↗