Browsing by Subject "Cancer models"

Now showing 1 - 5 of 5
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    Acoustofluidic assembly of primary tumor-derived organotypic cell clusters for rapid evaluation of cancer immunotherapy
    (BMC, 2023-02-04) Wu, Zhuhao; Ao, Zheng; Cai, Hongwei; Li, Xiang; Chen, Bin; Tu, Honglei; Wang, Yijie; Lu, Rongze Olivia; Gu, Mingxia; Cheng, Liang; Lu, Xin; Guo, Feng; Medicine, School of Medicine
    Cancer immunotherapy shows promising potential for treating breast cancer. While patients may have heterogeneous treatment responses for adjuvant therapy, it is challenging to predict an individual patient’s response to cancer immunotherapy. Here, we report primary tumor-derived organotypic cell clusters (POCCs) for rapid and reliable evaluation of cancer immunotherapy. By using a label-free, contactless, and highly biocompatible acoustofluidic method, hundreds of cell clusters could be assembled from patient primary breast tumor dissociation within 2 min. Through the incorporation of time-lapse living cell imaging, the POCCs could faithfully recapitulate the cancer-immune interaction dynamics as well as their response to checkpoint inhibitors. Superior to current tumor organoids that usually take more than two weeks to develop, the POCCs can be established and used for evaluation of cancer immunotherapy within 12 h. The POCCs can preserve the cell components from the primary tumor due to the short culture time. Moreover, the POCCs can be assembled with uniform fabricate size and cell composition and served as an open platform for manipulating cell composition and ratio under controlled treatment conditions with a short turnaround time. Thus, we provide a new method to identify potentially immunogenic breast tumors and test immunotherapy, promoting personalized cancer therapy.
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    Co-expression based cancer staging and application
    (Nature Publishing group, 2020-06-30) Yu, Xiangchun; Cao, Sha; Zhou, Yi; Yu, Zhezhou; Xu, Ying; Biochemistry and Molecular Biology, School of Medicine
    A novel method is developed for predicting the stage of a cancer tissue based on the consistency level between the co-expression patterns in the given sample and samples in a specific stage. The basis for the prediction method is that cancer samples of the same stage share common functionalities as reflected by the co-expression patterns, which are distinct from samples in the other stages. Test results reveal that our prediction results are as good or potentially better than manually annotated stages by cancer pathologists. This new co-expression-based capability enables us to study how functionalities of cancer samples change as they evolve from early to the advanced stage. New and exciting results are discovered through such functional analyses, which offer new insights about what functions tend to be lost at what stage compared to the control tissues and similarly what new functions emerge as a cancer advances. To the best of our knowledge, this new capability represents the first computational method for accurately staging a cancer sample.
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    Effective combinatorial immunotherapy for penile squamous cell carcinoma
    (Springer Nature, 2020-05-01) Huang, Tianhe; Cheng, Xi; Chahoud, Jad; Sarhan, Ahmed; Tamboli, Pheroze; Rao, Priya; Guo, Ming; Manyam, Ganiraju; Zhang, Li; Xiang, Yu; Han, Leng; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Lu, Xuemin; Feng, Shan; Ferrer, Magaly Martinez; Wang, Y. Alan; DePinho, Ronald A.; Pettaway, Curtis A.; Lu, Xin; Medicine, School of Medicine
    Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
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    Stromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent
    (Springer Nature, 2023-09-14) Kumar, Brijesh; Khatpe, Aditi S.; Guanglong, Jiang; Batic, Katie; Bhat-Nakshatri, Poornima; Granatir, Maggie M.; Addison, Rebekah Joann; Szymanski, Megan; Baldridge, Lee Ann; Temm, Constance J.; Sandusky, George; Althouse, Sandra K.; Cote, Michele L.; Miller, Kathy D.; Storniolo, Anna Maria; Nakshatri, Harikrishna; Surgery, School of Medicine
    The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to ductal epithelial cells in normal breasts of women of African ancestry compared to those of European ancestry. In this study, we demonstrate that these cells have properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRα and transdifferentiate into adipogenic and osteogenic lineages. PROCR + /ZEB1 + /PDGFRα+ (PZP) cells are enriched in normal breast tissues of women of African compared to European ancestry. PZP: epithelial cell communication results in luminal epithelial cells acquiring basal cell characteristics and IL-6-dependent increase in STAT3 phosphorylation. Furthermore, level of phospho-STAT3 is higher in normal and cancerous breast tissues of women of African ancestry. PZP cells transformed with HRasG12V ± SV40-T/t antigens generate metaplastic carcinoma suggesting that these cells are one of the cells-of-origin of metaplastic breast cancers.
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    USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model
    (Springer Nature, 2022) Kwon, Juntae; Choi, Hyeongjwa; Ware, Anna D.; Morillo, Bernadette Cecilia; Wang, Haiyang; Bouker, Kerrie B.; Lu, Xiongbin; Waldman, Todd; Han, Cecil; Medical and Molecular Genetics, School of Medicine
    Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes. Yet, its pathological contribution to ovarian tumorigenesis remains unknown. We crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer.