Biology subjects

Park, H. W.

Publications and source records attributed to Park, H. W..

6 recordsLinked to original sources

bioRxiv2025

Nutrient availability dictates cancer metabolism-based therapeutic responses of non-oncology drugs

Metabolic deregulation is a major hallmark of cancer, therefore, interventions that modify tumor nutrient availability are considered attractive adjuvants for improving clinical outcomes for cancer patients. Much work remains, however, in clarifying how the nutritional status of each patient can affect the metabolic vulnerability of drugs and inform individual medication guidelines. Working toward the goal of oncometabolic precision medicine, we introduce CM-SLP (cancer metabolism-based synthetic lethality platform), a high-throughput screening platform that explores the metabolic vulnerability of non-oncology drugs induced by altered nutrient availability and predicts the potential synthetic lethal interactions with either hyper- or hypo-nutrient conditions. We present promising CM-SLP candidates, such as propafenone and biguanides, as representative non-oncology drugs that cooperatively enhance cytotoxicity via dysregulated metabolic pathways. Furthermore, identifying mTOR and Hippo pathways as mediators of combined propafenone/hypoglycemia or biguanides/hypoglycemia treatments, respectively, we were able to circumvent the need for dietary interventions by administering the mTOR or TEAD inhibitors to induce energy stress and cancer cell death. Together, CM-SLP represents a critical step toward integrating metabolic profiling into precision oncology, offering novel therapeutic avenues tailored to individual patient needs.

cancer biology↗

bioRxiv2024

Adherent-to-suspension transition promotes melanoma metastatic dissemination

Melanoma is a highly metastatic skin cancer that often evades current therapeutic strategies primarily because of the complex mechanisms involved in metastasis. This study investigated the role of adherent-to-suspension transition (AST) in melanoma and its potential to facilitate metastasis by reprogramming cellular anchorage dependency. Using melanoma models, we demonstrated that the AST factors IKZF1, IRF8, and NFE2 are crucial for reprogramming, influencing gene expression related to cell adhesion and survival. Notably, our results highlight that AST factor expression undergoes dynamic changes during metastasis, which can be reversed in circulating tumor cells. Our findings revealed that AST contributes to the increased metastatic potential and invasiveness of melanoma cells and underscores its role independent of the epithelial-to-mesenchymal-like transition pathways. Based on the results, we highlight the potential of targeting AST mechanisms to develop new therapeutic strategies against metastasis.

cancer biology↗

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

Robust Methods For Quantifying Neuronal Morphology And Molecular Signaling Reveal That Psychedelics Do Not Induce Neuroplasticity

Induction of neuroplasticity has become the dominant explanatory framework for the rapid and sustained therapeutic effects of classic psychedelics. Within this broad concept, examination of morphological neuronal plasticity, such as dendritic arbor growth, is widely used to assess the neuroplasticity effects of classic and novel psychedelics. At the molecular level, it has been reported that serotonergic psychedelic compounds mediate dendritogenesis via the master molecular regulator of plasticity, TrkB, either directly via BDNF/TrkB signaling potentiation or indirectly through 5-HT2A receptor. To examine these hypotheses in detail, we developed a robust multimodal screening platform for unbiased, semi-automated quantification of cellular morphology and multiplex molecular signaling in the same cortical neurons. We found that in widely used primary neuronal cultures psychedelics do not directly modulate TrkB receptor or BDNF-TrkB signaling. We also found 5HT2a receptor gene expression and functional receptor levels are low, and psychedelics do not induce morphological growth, in contrast to significant dendritogenesis elicited by BDNF. Our results challenge recently published results in the field and indicate a need for rigorous experimental methods to study morphological manifestations of neuroplasticity effects induced by clinically used and experimental therapeutics.

neuroscience↗

bioRxiv2023

Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation

Adipocytes are crucial components of the tumor microenvironment (TME) that play a prominent role in supporting tumor growth. However, the characteristics of cancer-associated adipocytes (CAAs) that contribute to the pro-tumorigenic niche remain to be fully established. Here, we used adipocyte-specific Beclin1 KO (BaKO) mice to investigate the role of maladaptive adipocytes in promoting tumor progression. BECN1-deficient adipocytes exhibited downregulation of adipogenic markers and activation of YAP/TAZ signaling, similar to the traits observed in CAAs. Thus, we generated adipocyte-specific Becn1/Yap1/Taz KO mice, which exhibit markedly restored phenotypes in adipose tissue, resulting in tumor regression compared to that in BaKO. Further, we observed dysregulation of the BECN1-YAP/TAZ axis in the adipose tissue of mice fed a high-fat diet (HFD). Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Our findings provide insights into CAA formation and its significance in determining malignant TME, thereby suggesting a potential dual therapeutic strategy simultaneously targeting adipocyte homeostasis and cancer growth.

biochemistry↗

bioRxiv2023

Previous breeding success and carrion substrate together influence subsequent carrion choice by adult Nicrophorus vespilloides

Insects can adjust their behaviour in relation to experience in a wide range of contexts including foraging, mate selection, and choice of oviposition site. Here we investigate whether burying beetles modulate their choice of carrion in relation to the outcome of their past breeding experience. Burying beetles require small vertebrate carrion to reproduce. Beetle parents convert carrion into an edible nursery for their larvae, whom they typically care for throughout larval development. We tested whether a beetles past breeding experience influenced its subsequent choice of carrion, when presented simultaneously with either a dead mouse or a dead chick. We found that both male and female beetles favoured the same carrion as used in their first breeding attempt - but only if they had produced many larvae and only if they had previously bred on a mouse. Beetles that had produced fewer larvae on a dead mouse switched to favouring dead chicks in their second breeding attempt. Those that had bred on a dead chick chose carrion at random subsequently, regardless of their previous breeding success. Our general conclusion is that burying beetles can integrate different sources of information about their past breeding experience with current cues when selecting carrion for reproduction.

evolutionary biology↗