Chia-Hsin Hsu

All Publications

• A Translational Surgical Porcine Model for Postoperative Intra-Abdominal Adhesion Formation. Journal of visualized experiments : JoVE Reveron-Thornton, R. F., Hsu, C. H., Bobst, W., Guo, J. L., Meany, E. L., M Williams, C., Berry, C., Fallah, M., Korah, M., P Agolia, J., Guo, C., Fell, G. L., Hyun, J., Wan, D. C., Norton, J. A., Appel, E., Longaker, M. T., Delitto, D., Foster, D. S. 2026

  Abstract

  A porcine model of postoperative intra-abdominal adhesion formation was established using Yucatan mini pigs. The protocol combines midline laparotomy, small bowel resection with two-layer primary anastomosis, and a unilateral, parietal peritoneal abrasion in the format of an open abdominal surgical procedure. Adhesion formation was assessed four weeks postoperatively using established gross and histologic scoring criteria, with evaluations performed by blinded observers. Adhesions developed in all animals using this model and were multifocal, involving bowel loops, between the bowel and abdominal wall, involving the peritoneum overlying other organs in the abdomen (e.g. the liver), and operative sites, with variable severity. Histological analysis at four weeks demonstrated adhesions composed predominantly of extracellular matrix, fibroblasts, and blood vessels, consistent with a remodeling-phase wound healing tissue phenotype. This model is relevant for the study of abdominal adhesion fibrosis biology and/or the translational evaluation of candidate anti-adhesion therapeutics. By integrating a clinically relevant intestinal surgical procedure with a defined peritoneal injury and a standardized assessment strategy, this protocol provides a reproducible approach for inducing and evaluating postoperative intra-abdominal adhesions in a large animal model.

  View details for DOI 10.3791/70377

  View details for PubMedID 41911229

• Therapy-Induced ECM Remodeling Creates a Transient Immune Barrier in Residual Melanoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Hsu, C. H., Chen, J., Lee, K. J., Donahue, L. R., Kacaj, D., McDonough, S. P., White, A. C. 2025; 12 (42): e08451

  Abstract

  Targeted therapies reshape the tumor not only by eliminating malignant cells but also by altering the stromal and immunologic adaptations that emerge during treatment, which remain incompletely defined. Here, extracellular matrix (ECM) remodeling is identified as a key driver of immune exclusion during the residual disease phase-a transient, therapy-tolerant state that precedes overt resistance. Using an immune-competent melanoma model and temporal transcriptomic profiling of tumor cells and fibroblasts, a coordinated induction of ECM-related genes, particularly collagen, is uncovered during the development of residual disease. This remodeling creates a physical barrier that spatially excludes CD8⁺ T cells from residual tumor niches, compromising immune surveillance. Human melanoma datasets validate increased ECM gene expression and show an inverse correlation between collagen and cytotoxic T lymphocyte infiltration, as well as patient survival. Strikingly, pharmacologic inhibition of collagen deposition, administered at the point of maximal tumor regression, restores CD8⁺ T cell infiltration and delays resistance in a CD8⁺ T cell-dependent manner. These findings define residual disease as a therapeutically actionable stromal state and demonstrate that ECM modulation can overcome immune exclusion, thereby improving the durability of targeted therapy responses.

  View details for DOI 10.1002/advs.202508451

  View details for PubMedID 40847444

  View details for PubMedCentralID PMC12622497

• The Lysosome in Malignant Melanoma: Biology, Function and Therapeutic Applications. Cells Hsu, C. H., Lee, K. J., Chiu, Y. H., Huang, K. C., Wang, G. S., Chen, L. P., Liao, K. W., Lin, C. S. 2022; 11 (9)

  Abstract

  Lysosomes are membrane-bound vesicles that play roles in the degradation and recycling of cellular waste and homeostasis maintenance within cells. False alterations of lysosomal functions can lead to broad detrimental effects and cause various diseases, including cancers. Cancer cells that are rapidly proliferative and invasive are highly dependent on effective lysosomal function. Malignant melanoma is the most lethal form of skin cancer, with high metastasis characteristics, drug resistance, and aggressiveness. It is critical to understand the role of lysosomes in melanoma pathogenesis in order to improve the outcomes of melanoma patients. In this mini-review, we compile our current knowledge of lysosomes' role in tumorigenesis, progression, therapy resistance, and the current treatment strategies related to lysosomes in melanoma.

  View details for DOI 10.3390/cells11091492

  View details for PubMedID 35563798

  View details for PubMedCentralID PMC9103375

• KRAS-dependent cancer cells promote survival by producing exosomes enriched in Survivin CANCER LETTERS Chang, W., Nguyen, T., Hsu, C., Bryant, K. L., Kim, H., Ying, H., Erickson, J. W., Der, C. J., Cerione, R. A., Antonyak, M. A. 2021; 517: 66-77

  Abstract

  Mutations in KRAS frequently occur in human cancer and are especially prevalent in pancreatic ductal adenocarcinoma (PDAC), where they have been shown to promote aggressive phenotypes. However, targeting this onco-protein has proven to be challenging, highlighting the need to further identify the various mechanisms used by KRAS to drive cancer progression. Here, we considered the role played by exosomes, a specific class of extracellular vesicles (EVs) derived from the endocytic cellular trafficking machinery, in mediating the ability of KRAS to promote cell survival. We found that exosomes isolated from the serum of PDAC patients, as well as from KRAS-transformed fibroblasts and pancreatic cancer cells, were all highly enriched in the cell survival protein Survivin. Exosomes containing Survivin, upon engaging serum-starved cells, strongly enhanced their survival. Moreover, they significantly compromised the effectiveness of the conventional chemotherapy drug paclitaxel, as well as a novel therapy that combines an ERK inhibitor with chloroquine, which is currently in clinical trials for PDAC. The survival benefits provided by oncogenic KRAS-derived exosomes were markedly reduced when depleted of Survivin using siRNA or upon treatment with the Survivin inhibitor YM155. Taken together, these findings demonstrate how KRAS mutations give rise to exosomes that provide a unique form of intercellular communication to promote cancer cell survival and therapy resistance, as well as raise interesting possibilities regarding their potential for serving as therapeutic targets and diagnostic markers for KRAS-dependent cancers.

  View details for DOI 10.1016/j.canlet.2021.05.031

  View details for Web of Science ID 000678522800003

  View details for PubMedID 34111513

  View details for PubMedCentralID PMC8324551

• Genome-wide DNA methylation analysis using MethylCap-seq in canine high-grade B-cell lymphoma. Journal of leukocyte biology Hsu, C. H., Tomiyasu, H., Lee, J. J., Tung, C. W., Liao, C. H., Chuang, C. H., Huang, L. Y., Liao, K. W., Chou, C. H., Liao, A. T., Lin, C. S. 2021; 109 (6): 1089-1103

  Abstract

  DNA methylation is a comprehensively studied epigenetic modification and plays crucial roles in cancer development. In the present study, MethylCap-seq was used to characterize the genome-wide DNA methylation patterns in canine high-grade B-cell lymphoma (cHGBL). Canine methylated DNA fragments were captured and the MEDIUM-HIGH and LOW fraction of methylated DNA was obtained based on variation in CpG methylation density. In the MEDIUM-HIGH and LOW fraction, 2144 and 1987 cHGBL-specific hypermethylated genes, respectively, were identified. Functional analysis highlighted pathways strongly related to oncogenesis. The relevant signaling pathways associated with neuronal system were also revealed, echoing recent novel findings that neurogenesis plays key roles in tumor establishment. In addition, 14 genes were hypermethylated in all the cHGBL cases but not in the healthy dogs. These genes might be potential signatures for tracing cHGBL, and some of them have been reported to play roles in various types of cancers. Further, the distinct methylation pattern of cHGBL showed a concordance with the clinical outcome, suggesting that aberrant epigenetic changes may influence tumor behavior. In summary, our study characterized genome-wide DNA methylation patterns using MethylCap-seq in cHGBL; the findings suggest that specific DNA hypermethylation holds promise for dissecting tumorigenesis and uncovering biomarkers for monitoring the progression of cHGBL.

  View details for DOI 10.1002/JLB.2A0820-673R

  View details for PubMedID 33031589

• Genome-wide DNA methylation and RNA-seq analyses identify genes and pathways associated with doxorubicin resistance in a canine diffuse large B-cell lymphoma cell line. PloS one Hsu, C. H., Tomiyasu, H., Liao, C. H., Lin, C. S. 2021; 16 (5): e0250013

  Abstract

  Doxorubicin resistance is a major challenge in the successful treatment of canine diffuse large B-cell lymphoma (cDLBCL). In the present study, MethylCap-seq and RNA-seq were performed to characterize the genome-wide DNA methylation and differential gene expression patterns respectively in CLBL-1 8.0, a doxorubicin-resistant cDLBCL cell line, and in CLBL-1 as control, to investigate the underlying mechanisms of doxorubicin resistance in cDLBCL. A total of 20289 hypermethylated differentially methylated regions (DMRs) were detected. Among these, 1339 hypermethylated DMRs were in promoter regions, of which 24 genes showed an inverse correlation between methylation and gene expression. These 24 genes were involved in cell migration, according to gene ontology (GO) analysis. Also, 12855 hypermethylated DMRs were in gene-body regions. Among these, 353 genes showed a positive correlation between methylation and gene expression. Functional analysis of these 353 genes highlighted that TGF-β and lysosome-mediated signal pathways are significantly associated with the drug resistance of CLBL-1. The tumorigenic role of TGF-β signaling pathway in CLBL-1 8.0 was further validated by treating the cells with a TGF-β inhibitor(s) to show the increased chemo-sensitivity and intracellular doxorubicin accumulation, as well as decreased p-glycoprotein expression. In summary, the present study performed an integrative analysis of DNA methylation and gene expression in CLBL-1 8.0 and CLBL-1. The candidate genes and pathways identified in this study hold potential promise for overcoming doxorubicin resistance in cDLBCL.

  View details for DOI 10.1371/journal.pone.0250013

  View details for PubMedID 33961622

  View details for PubMedCentralID PMC8104391

• Immune cell shuttle for precise delivery of nanotherapeutics for heart disease and cancer. Science advances Huang, S. S., Lee, K. J., Chen, H. C., Prajnamitra, R. P., Hsu, C. H., Jian, C. B., Yu, X. E., Chueh, D. Y., Kuo, C. W., Chiang, T. C., Choong, O. K., Huang, S. C., Beh, C. Y., Chen, L. L., Lai, J. J., Chen, P., Kamp, T. J., Tien, Y. W., Lee, H. M., Hsieh, P. C. 2021; 7 (17)

  Abstract

  The delivery of therapeutics through the circulatory system is one of the least arduous and less invasive interventions; however, this approach is hampered by low vascular density or permeability. In this study, by exploiting the ability of monocytes to actively penetrate into diseased sites, we designed aptamer-based lipid nanovectors that actively bind onto the surface of monocytes and are released upon reaching the diseased sites. Our method was thoroughly assessed through treating two of the top causes of death in the world, cardiac ischemia-reperfusion injury and pancreatic ductal adenocarcinoma with or without liver metastasis, and showed a significant increase in survival and healing with no toxicity to the liver and kidneys in either case, indicating the success and ubiquity of our platform. We believe that this system provides a new therapeutic method, which can potentially be adapted to treat a myriad of diseases that involve monocyte recruitment in their pathophysiology.

  View details for DOI 10.1126/sciadv.abf2400

  View details for PubMedID 33893103

  View details for PubMedCentralID PMC8064633

• Inducing a Transient Increase in Blood-Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme. ACS nano Lundy, D. J., Lee, K. J., Peng, I. C., Hsu, C. H., Lin, J. H., Chen, K. H., Tien, Y. W., Hsieh, P. C. 2019; 13 (1): 97-113

  Abstract

  The blood-brain barrier (BBB) selectively controls the passage of endogenous and exogenous molecules between systemic circulation and the brain parenchyma. Nanocarrier-based drugs such as liposomes and nanoparticles are an attractive prospect for cancer therapy since they can carry a drug payload and be modified to improve targeting and retention at the desired site. However, the BBB prevents most therapeutic drugs from entering the brain, including physically restricting the passage of liposomes and nanoparticles. In this paper, we show that a low dose of systemically injected recombinant human vascular endothelial growth factor induces a short period of increased BBB permeability. We have shown increased delivery of a range of nanomedicines to the brain including contrast agents for imaging, varying sizes of nanoparticles, small molecule chemotherapeutics, tracer dyes, and liposomal chemotherapeutics. However, this effect was not uniform across all brain regions, and permeability varied depending on the drug or molecule measured. We have found that this window of BBB permeability effect is transient, with normal BBB integrity restored within 4 h. This strategy, combined with liposomal doxorubicin, was able to significantly extend survival in a mouse model of human glioblastoma. We have found no evidence of systemic toxicity, and the technique was replicated in pigs, demonstrating that this technique could be scaled up and potentially be translated to the clinic, thus allowing the use of nanocarrier-based therapies for brain disorders.

  View details for DOI 10.1021/acsnano.8b03785

  View details for PubMedID 30532951