Browsing by Author "Natesh, Naveen R"

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    Patient-derived micro-organospheres enable clinical precision oncology.
    (Cell stem cell, 2022-06) Ding, Shengli; Hsu, Carolyn; Wang, Zhaohui; Natesh, Naveen R; Millen, Rosemary; Negrete, Marcos; Giroux, Nicholas; Rivera, Grecia O; Dohlman, Anders; Bose, Shree; Rotstein, Tomer; Spiller, Kassandra; Yeung, Athena; Sun, Zhiguo; Jiang, Chongming; Xi, Rui; Wilkin, Benjamin; Randon, Peggy M; Williamson, Ian; Nelson, Daniel A; Delubac, Daniel; Oh, Sehwa; Rupprecht, Gabrielle; Isaacs, James; Jia, Jingquan; Chen, Chao; Shen, John Paul; Kopetz, Scott; McCall, Shannon; Smith, Amber; Gjorevski, Nikolche; Walz, Antje-Christine; Antonia, Scott; Marrer-Berger, Estelle; Clevers, Hans; Hsu, David; Shen, Xiling
    Patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here, we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of micro-organospheres (MOSs) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology. A clinical study of recently diagnosed metastatic colorectal cancer (CRC) patients using an MOS-based precision oncology pipeline reliably assessed tumor drug response within 14 days, a timeline suitable for guiding treatment decisions in the clinic. Furthermore, MOSs capture original stromal cells and allow T cell penetration, providing a clinical assay for testing immuno-oncology (IO) therapies such as PD-1 blockade, bispecific antibodies, and T cell therapies on patient tumors.
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    Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection.
    (JCI insight, 2020-10) Dangi, Anil; Natesh, Naveen R; Husain, Irma; Ji, Zhicheng; Barisoni, Laura; Kwun, Jean; Shen, Xiling; Thorp, Edward B; Luo, Xunrong
    Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl, a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with Axl gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.