Zumana Khair

All Publications

• Single-cell spatial proteomic imaging for human neuropathology. Acta neuropathologica communications Vijayaragavan, K., Cannon, B. J., Tebaykin, D., Bosse, M., Baranski, A., Oliveria, J. P., Bukhari, S. A., Mrdjen, D., Corces, M. R., McCaffrey, E. F., Greenwald, N. F., Sigal, Y., Marquez, D., Khair, Z., Bruce, T., Goldston, M., Bharadwaj, A., Montine, K. S., Angelo, R. M., Montine, T. J., Bendall, S. C. 2022; 10 (1): 158

  Abstract

  Neurodegenerative disorders are characterized by phenotypic changes and hallmark proteopathies. Quantifying these in archival human brain tissues remains indispensable for validating animal models and understanding disease mechanisms. We present a framework for nanometer-scale, spatial proteomics with multiplex ion beam imaging (MIBI) for capturing neuropathological features. MIBI facilitated simultaneous, quantitative imaging of 36 proteins on archival human hippocampus from individuals spanning cognitively normal to dementia. Customized analysis strategies identified cell types and proteopathies in the hippocampus across stages of Alzheimer's disease (AD) neuropathologic change. We show microglia-pathologic tau interactions in hippocampal CA1 subfield in AD dementia. Data driven, sample independent creation of spatial proteomic regions identified persistent neurons in pathologic tau neighborhoods expressing mitochondrial protein MFN2, regardless of cognitive status, suggesting a survival advantage. Our study revealed unique insights from multiplexed imaging and data-driven approaches for neuropathologic analysis and serves broadly as a methodology for spatial proteomic analysis of archival human neuropathology. TEASER: Multiplex Ion beam Imaging enables deep spatial phenotyping of human neuropathology-associated cellular and disease features.

  View details for DOI 10.1186/s40478-022-01465-x

  View details for PubMedID 36333818

• Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma. Cell Risom, T., Glass, D. R., Averbukh, I., Liu, C. C., Baranski, A., Kagel, A., McCaffrey, E. F., Greenwald, N. F., Rivero-Gutiérrez, B., Strand, S. H., Varma, S., Kong, A., Keren, L., Srivastava, S., Zhu, C., Khair, Z., Veis, D. J., Deschryver, K., Vennam, S., Maley, C., Hwang, E. S., Marks, J. R., Bendall, S. C., Colditz, G. A., West, R. B., Angelo, M. 2022; 185 (2): 299-310.e18

  Abstract

  Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.

  View details for DOI 10.1016/j.cell.2021.12.023

  View details for PubMedID 35063072

• Key Players and Potential Therapies in the Development of Breast Cancer Metastasis to the Spine Key Players and Potential Therapies in the Development of Breast Cancer Metastasis to the Spine Khair , Z., Mouhtouris, E., Gregory, J., Quan, G. 2022; 10 (1)
• Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells Nature Biotechnology Hartmann, F., Mrdien, D., McCaffrey, E., Glass, D. R., Greenwald, N. F., Bharadwaj, A., Khair, Z., Baranski, A., Baskar, R., Bendall, M., Bendall, S. C. 2021

  View details for DOI 10.1101/2020.01.17.909796

• Spatio-temporal coordination at the maternal-fetal interface promotes trophoblast invasion and vascular remodeling in the first half of human pregnancy In Review Greenbaum, S., Averbukh, I., Soon, E., Rizzuto, G., Baranski, A., Greenwald, N., Bosse, M., Jaswa, E. G., Khair, Z., Kwok, S., Warshawsky, S., Miller, G., Schwartz, M., Graf, W., Valen, D. V., Keren, L., Hollmann, T., Rijn, M., Angelo, M. 2021

  View details for DOI 10.1101/2021.09.08.459490

• In-depth characterization of immune cells in preeclampsia using Multiplexed Ion Beam Imaging by Time-of-Flight (MIBI-TOF) Greenbaum, S., Bosse, M., Baranski, A., Khair, Z., Bruce, T., Tebaykin, D., Oliveria, J., Bendall, S. C., Winn, V. D., Angelo, M. MOSBY-ELSEVIER. 2020: S156–S157

  View details for DOI 10.1016/j.ajog.2019.11.241

  View details for Web of Science ID 000504997300225

• Single-cell metabolic profiling of human cytotoxic T cells. Nature biotechnology Hartmann, F. J., Mrdjen, D. n., McCaffrey, E. n., Glass, D. R., Greenwald, N. F., Bharadwaj, A. n., Khair, Z. n., Verberk, S. G., Baranski, A. n., Baskar, R. n., Graf, W. n., Van Valen, D. n., Van den Bossche, J. n., Angelo, M. n., Bendall, S. C. 2020

  Abstract

  Cellular metabolism regulates immune cell activation, differentiation and effector functions, but current metabolic approaches lack single-cell resolution and simultaneous characterization of cellular phenotype. In this study, we developed an approach to characterize the metabolic regulome of single cells together with their phenotypic identity. The method, termed single-cell metabolic regulome profiling (scMEP), quantifies proteins that regulate metabolic pathway activity using high-dimensional antibody-based technologies. We employed mass cytometry (cytometry by time of flight, CyTOF) to benchmark scMEP against bulk metabolic assays by reconstructing the metabolic remodeling of in vitro-activated naive and memory CD8+ T cells. We applied the approach to clinical samples and identified tissue-restricted, metabolically repressed cytotoxic T cells in human colorectal carcinoma. Combining our method with multiplexed ion beam imaging by time of flight (MIBI-TOF), we uncovered the spatial organization of metabolic programs in human tissues, which indicated exclusion of metabolically repressed immune cells from the tumor-immune boundary. Overall, our approach enables robust approximation of metabolic and functional states in individual cells.

  View details for DOI 10.1038/s41587-020-0651-8

  View details for PubMedID 32868913

• TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis. Life science alliance Baskar, R., Fienberg, H. G., Khair, Z., Favaro, P., Kimmey, S., Green, D. R., Nolan, G. P., Plevritis, S., Bendall, S. C. 2019; 2 (6)

  Abstract

  TNFalpha-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity in cellular signaling responses to TRAIL, linking it to apoptotic frequency across numerous cell systems with single-cell mass cytometry (CyTOF). Although all cells respond to TRAIL, a variable fraction persists without apoptotic progression. This cell-specific behavior is nonheritable where both the TRAIL-induced signaling responses and frequency of apoptotic resistance remain unaffected by prior exposure. The diversity of signaling states upon exposure is correlated to TRAIL resistance. Concomitantly, constricting the variation in signaling response with kinase inhibitors proportionally decreases TRAIL resistance. Simultaneously, TRAIL-induced de novo translation in resistant cells, when blocked by cycloheximide, abrogated all TRAIL resistance. This work highlights how cell signaling diversity, and subsequent translation response, relates to nonheritable fractional escape from TRAIL-induced apoptosis. This refined view of TRAIL resistance provides new avenues to study death ligands in general.

  View details for DOI 10.26508/lsa.201900554

  View details for PubMedID 31704709