Daniel Dan Liu

All Publications

• Purification and characterization of human neural stem and progenitor cells. Cell Liu, D. D., He, J. Q., Sinha, R., Eastman, A. E., Toland, A. M., Morri, M., Neff, N. F., Vogel, H., Uchida, N., Weissman, I. L. 2023; 186 (6): 1179

  Abstract

  The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.

  View details for DOI 10.1016/j.cell.2023.02.017

  View details for PubMedID 36931245

• Scalable single-cell total RNA sequencing unifies coding and noncoding transcriptomics. Nature biotechnology Isakova, A., Liu, D. D., Cvijović, I., Sinha, R., Eastman, A. E., Saul, S., Detweiler, A. M., Neff, N., Einav, S., Weissman, I. L., Quake, S. R. 2026

  Abstract

  Current single-cell RNA atlases largely capture polyadenylated transcripts while missing critical regulatory layers from noncoding RNA. To address this, we develop a generalizable framework that adapts total RNA profiling for use in standard droplet-based platforms and captures a broad complement of coding and noncoding RNAs using a unified pipeline. Applying this approach to the developing human brain, we generate a dataset mapping diverse RNA biotypes across all neuronal and non-neuronal lineages, revealing biotype-specific expression programs with cell-type and temporal specificity. Tracking microRNA dynamics in Cajal-Retzius neurons, transient and early-born neurons in the cortex, we show the enrichment and target anticorrelation of MIR137, associated with schizophrenia and intellectual disability, suggesting tight regulatory control. We apply TotalX to human peripheral blood mononuclear cells and identify transcriptional modules combining coding and noncoding RNAs and tRNA dynamics. In addition, we analyze dengue-infected hepatocytes and capture non-adenylated viral transcripts that distinguish infection states. This expanded coverage helps with understanding cellular identity and gene regulation at the atlas scale.

  View details for DOI 10.1038/s41587-026-03068-6

  View details for PubMedID 41917462

  View details for PubMedCentralID 10213152

• Xenophagocytosis blockade enhances interspecies chimerism. bioRxiv : the preprint server for biology Wang, S., Niizuma, K., Liu, D. D., Suchy, F. P., Sato, H., Yanagida, A., Masaki, H., Miyauchi, M., Tabatabaee, S., Hidajat, N., Bhadury, J., Charlesworth, C. T., Zhang, J., Weissman, I. L., Nakauchi, H. 2025

  Abstract

  Organ shortage remains a major challenge in transplantation medicine. Interspecies blastocyst complementation is a promising approach to generate human organs in livestock hosts. However, getting xenogeneic donor cells to engraft and expand at early stages remains challenging. Here we identify an innate immune barrier, wherein host macrophages selectively recognize and eliminate viable xenogeneic donor cells. These events represent a form of phagoptosis and highlight a xenogeneic clearance process that we term xenophagocytosis. We identify the mechanism by which host macrophages selectively phagocytize xenogeneic donor cells: xenogeneic cells display elevated phosphatidylserine, an "eat-me" signal recognized by host macrophages through phagocytic receptor Axl. Xenophagocytosis blockade improves both rat and human donor chimerism in mouse embryos, indicating a conserved mechanism. These findings reveal potential mechanisms by which innate immune cells eliminate xenogeneic cells in early embryogenesis to preserve species integrity and offer improved strategies for generating human organs in livestock.

  View details for DOI 10.1101/2025.10.14.682291

  View details for PubMedID 41279269

  View details for PubMedCentralID PMC12633007

• Germline stem cell isolation, lineage tracing, and aging in a protochordate. bioRxiv : the preprint server for biology Levy, T., Anselmi, C., Ishizuka, K. J., Gordon, T., Voskoboynik, Y., McGeever, E., Detweiler, A. M., Levin, L., Palmeri, K. J., Liu, D. D., Sinha, R., Ohene-Gambill, B. F., Raveh, T., Morri, M., Vanni, V., Manni, L., Sahoo, D., Neff, N. F., Rosental, B., Weissman, I. L., Voskoboynik, A. 2025

  Abstract

  Germline stem cells (GSCs), the source of gametes, are the only stem cells capable of passing genes to future generations and are therefore considered units of natural selection. Yet, the factors that influence GSC fitness, and thus govern GSC competition, which exist in both protochordates and mammals, remain poorly understood. We studied how aging affects GSC fitness in the protochordate Botryllus schlosseri, an evolutionary crosspoint between invertebrates and vertebrates. GSCs were isolated and distinguished from developing and mature gametes using flow cytometry and scRNA-Seq, facilitated by a new PacBio genome assembly. Moreover, their function was validated through a novel lineage tracing approach that combines membrane-labeled GSC transplantation with scRNA-Seq. Leveraging our method to isolate them, single-cell transcriptomics showed significant age-related changes between young and old GSCs. Spermatids and sperm, however, showed minimal changes, suggesting that reproductive aging is governed by GSCs rather than by gametes. Reduced expressions of markers like DDX4 and PIWIL1 in aged GSCs mirrored trends in mammalian datasets, pointing to a conserved GSC-driven aging mechanism across chordate evolution. This study provides new techniques that lay the foundation to investigate further drivers of GSC fitness and highlights fertility-related genes as promising targets for therapies to preserve reproductive health.

  View details for DOI 10.1101/2025.08.31.673173

  View details for PubMedID 40949951

• Modeling glioma intratumoral heterogeneity with primary human neural stem and progenitor cells. Stem cell reports Liu, D. D., Gao, D., Womack-Gambrel, N. L., Eastman, A. E., Ohene-Gambill, B. F., Weissman, I. L. 2025: 102597

  Abstract

  Gliomas are notorious for their intratumoral heterogeneity, which drives therapy resistance. Glioma tumor cells mimic a neural stem cell (NSC) hierarchy reminiscent of normal brain development. How intratumoral heterogeneity is shaped by cell-of-origin and various driver mutations is not fully understood. We develop a model of glioma initiation using neural stem and progenitor cells (NSPCs) purified from midgestational human brain tissue, including tripotent NSCs, bipotent glial progenitor cells (GPCs), and unipotent oligodendrocyte progenitor cells (OPCs). We transduced these isogenic lines with defined combinations of oncogenic drivers (TP53, NF1, CDK4, EGFR, and PDGFRA) and transplanted them into mice. We find that OPC-derived tumors harbored a higher proportion of differentiated oligodendrocyte-like cells, reminiscent of low-grade oligodendrogliomas. CDK4 drove a neuron-like subtype, while EGFR drove a GPC-like subtype. Our platform is highly adaptable and allows for modular and systematic interrogation of how cell-of-origin and specific driver mutations shape the tumor landscape.

  View details for DOI 10.1016/j.stemcr.2025.102597

  View details for PubMedID 40749669

• Human skeletal development and regeneration are shaped by functional diversity of stem cells across skeletal sites. Cell stem cell Ambrosi, T. H., Taheri, S., Chen, K., Sinha, R., Wang, Y., Hunt, E. J., Goodnough, L. H., Murphy, M. P., Steininger, H. M., Hoover, M. Y., Felix, F., Weldon, K. C., Koepke, L. S., Sokol, J., Liu, D. D., Zhao, L., Conley, S. D., Lu, W. J., Morri, M., Neff, N. F., Van Rysselberghe, N. L., Wheeler, E. E., Wang, Y., Leach, J. K., Saiz, A., Wang, A., Yang, G. P., Goodman, S., Bishop, J. A., Gardner, M. J., Wan, D. C., Weissman, I. L., Longaker, M. T., Sahoo, D., Chan, C. K. 2025

  Abstract

  The skeleton is one of the most structurally and compositionally diverse organ systems in the human body, depending on unique cellular dynamisms. Here, we integrate prospective isolation of human skeletal stem cells (hSSCs; CD45-CD235a-TIE2-CD31-CD146-PDPN+CD73+CD164+) from ten skeletal sites with functional assays and single-cell RNA sequencing (scRNA-seq) analysis to identify chondrogenic, osteogenic, stromal, and fibrogenic subtypes of hSSCs during development and their linkage to skeletal phenotypes. We map the distinct composition of hSSC subtypes across multiple skeletal sites and demonstrate their unique in vivo clonal dynamics. We find that age-related changes in bone formation and regeneration disorders stem from a pathological fibroblastic shift in the hSSC pool. Utilizing a Boolean algorithm, we uncover gene regulatory networks that dictate differences in the ability of hSSCs to generate specific skeletal tissues. Importantly, hSSC lineage dynamics are pharmacologically malleable, providing a new strategy to treat aberrant hSSC diversity central to aging and skeletal maladies.

  View details for DOI 10.1016/j.stem.2025.02.013

  View details for PubMedID 40118065

• Dual Fresh/Fixed Tissue Workflow for Novel Cell Type Validation in Human Brains Donated for Rapid Research Autopsy Reilly, E., Eastman, A., Womack, N., Belk, J., Liu, D., Raj, S., Jaiswal, S., Weissman, I., Hooper, J. ELSEVIER SCIENCE INC. 2025

  View details for DOI 10.1016/j.labinv.2024.102240

  View details for Web of Science ID 001465603400018

• Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung. The Journal of experimental medicine Wu, T. T., Travaglini, K. J., Rustagi, A., Xu, D., Zhang, Y., Andronov, L., Jang, S., Gillich, A., Dehghannasiri, R., Martinez-Colon, G. J., Beck, A., Liu, D. D., Wilk, A. J., Morri, M., Trope, W. L., Bierman, R., Weissman, I. L., Shrager, J. B., Quake, S. R., Kuo, C. S., Salzman, J., Moerner, W. E., Kim, P. S., Blish, C. A., Krasnow, M. A. 2024; 221 (6)

  Abstract

  Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.

  View details for DOI 10.1084/jem.20232192

  View details for PubMedID 38597954

• Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells. Developmental cell Fowler, J. L., Zheng, S. L., Nguyen, A., Chen, A., Xiong, X., Chai, T., Chen, J. Y., Karigane, D., Banuelos, A. M., Niizuma, K., Kayamori, K., Nishimura, T., Cromer, M. K., Gonzalez-Perez, D., Mason, C., Liu, D. D., Yilmaz, L., Miquerol, L., Porteus, M. H., Luca, V. C., Majeti, R., Nakauchi, H., Red-Horse, K., Weissman, I. L., Ang, L. T., Loh, K. M. 2024

  Abstract

  The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.

  View details for DOI 10.1016/j.devcel.2024.03.003

  View details for PubMedID 38569552

• Prospective isolation of neural stem and progenitor cells from the developing human brain. STAR protocols Liu, D. D., He, J. Q., Uchida, N., Weissman, I. L., Sinha, R. 2023; 4 (4): 102674

  Abstract

  Prospective isolation of defined cell types is critical for the functional study of stem cells, especially in primary human tissues. Here, we present a protocol for purifying 10 transcriptomically and functionally distinct neural stem and progenitor cell types from the developing human brain using fluorescence-activated cell sorting. We describe steps for tissue dissociation, staining, and cell sorting as well as downstream functional experiments for measuring clonogenicity, differentiation, and engraftment potential of purified populations. For complete details on the use and execution of this protocol, please refer to Liu etal. (2023).1.

  View details for DOI 10.1016/j.xpro.2023.102674

  View details for PubMedID 37897731

• LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer. Nature cancer Perez-Nunez, I., Rozalen, C., Palomeque, J. A., Sangrador, I., Dalmau, M., Comerma, L., Hernandez-Prat, A., Casadevall, D., Menendez, S., Liu, D. D., Shen, M., Berenguer, J., Ruiz, I. R., Pena, R., Montanes, J. C., Alba, M. M., Bonnin, S., Ponomarenko, J., Gomis, R. R., Cejalvo, J. M., Servitja, S., Marzese, D. M., Morey, L., Voorwerk, L., Arribas, J., Bermejo, B., Kok, M., Pusztai, L., Kang, Y., Albanell, J., Celia-Terrassa, T. 2022

  Abstract

  Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.

  View details for DOI 10.1038/s43018-022-00339-4

  View details for PubMedID 35301507

• Mesenchymal stromal cells for the treatment of Alzheimer's disease: Strategies and limitations. Frontiers in molecular neuroscience Regmi, S., Liu, D. D., Shen, M., Kevadiya, B. D., Ganguly, A., Primavera, R., Chetty, S., Yarani, R., Thakor, A. S. 2022; 15: 1011225

  Abstract

  Alzheimer's disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient's ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors to promote the survival of neurons, but they also transfer functional mitochondria and miRNAs to boost their bioenergetic profile as well as improve microglial clearance of accumulated protein aggregates. This review focuses on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.

  View details for DOI 10.3389/fnmol.2022.1011225

  View details for PubMedID 36277497

• A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2 Induced Glycolytic Reprogramming in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Beinat, C., Patel, C. B., Haywood, T., Murty, S., Naya, L., Castillo, J. B., Reyes, S. T., Phillips, M., Buccino, P., Shen, B., Park, J. H., Koran, M. E., Alam, I. S., James, M. L., Holley, D., Halbert, K., Gandhi, H., He, J. Q., Granucci, M., Johnson, E., Liu, D. D., Uchida, N., Sinha, R., Chu, P., Born, D. E., Warnock, G. I., Weissman, I., Hayden Gephart, M., Khalighi, M. M., Massoud, T. F., Iagaru, A., Davidzon, G., Thomas, R., Nagpal, S., Recht, L. D., Gambhir, S. S. 2021

  Abstract

  PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients.EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 {plus minus} 29.58 GBq/mol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients.RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 {plus minus} 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [18F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation.CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

  View details for DOI 10.1158/1078-0432.CCR-21-0544

  View details for PubMedID 34475101

• Trends in the characteristics of human functional genomic data on the gene expression omnibus, 2001-2017. Laboratory investigation; a journal of technical methods and pathology Liu, D. D., Zhang, L. 2019; 99 (1): 118-127

  Abstract

  The gene expression omnibus (GEO) is the world's largest public repository of functional genomic data. Despite its broad use in secondary genomic analyses, the temporal trends in the characteristics of genomic data on GEO, including experimental procedures, geographic origin, funder(s), and related disease, have not been examined. We identified 75,376 Series deposited to the GEO during 2001-2017 and built a database of all human genomic data (39,076 Series, 51.8% of all Series). Using the associated publications, we obtained funding information and identified the related disease area. Of the Series with classified disease areas, the two most common were cancer (n = 12,688, 32.5%) and immunologic diseases (n = 2,393, 6.1%), while the percentages of all other disease areas were below 5%, including neurological diseases (n = 1733, 4.4%), infectious diseases (n = 1225, 3.1%), diabetes (n = 828, 2.1%), and cardiovascular diseases (n = 299, 0.8%). In recent years, there has been a significant increase in the use of high-throughput sequencing (HTS), protein array and multiple-platform technologies, as well as in the proportion of North American deposits. Compared to those from other regions, North American deposits appeared to lead the shift from array-based to HTS technologies (odds ratio [OR], 95% confidence intervals [CI] = 3.39, 3.23-3.55, P = 9.40E-323), and were less likely to focus on a major disease area (OR = 0.64, 95% CI: 0.61-0.67, P = 5.02E-107), suggesting a greater emphasis on basic science in North America. Furthermore, the Series utilizing HTS were less likely to be disease-classified compared to other technologies (OR = 0.39, 95% CI: 0.37-0.41, P = 1.00E-322), suggesting a preferential use or adoption of HTS in basic science settings. Finally, funding from the NHGRI, NCI, NIEHS, and NCCR resulted in a higher number of GEO Series per grant than other NIH institutes, demonstrating different preferences on genomic studies among awardees of NIH institutes. Our findings demonstrate geographic, technological, and funding disparities in the trends of GEO deposit characteristics.

  View details for DOI 10.1038/s41374-018-0125-5

  View details for PubMedID 30206311

• Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience Ullah, M. n., Liu, D. D., Thakor, A. S. 2019; 15: 421–38

  Abstract

  Mesenchymal stromal cells (MSCs) have been widely investigated for their therapeutic potential in regenerative medicine, owing to their ability to home damaged tissue and serve as a reservoir of growth factors and regenerative molecules. As such, clinical applications of MSCs are reliant on these cells successfully migrating to the desired tissue following their administration. Unfortunately, MSC homing is inefficient, with only a small percentage of cells reaching the target tissue following systemic administration. This attrition represents a major bottleneck in realizing the full therapeutic potential of MSC-based therapies. Accordingly, a variety of strategies have been employed in the hope of improving this process. Here, we review the molecular mechanisms underlying MSC homing, based on a multistep model involving (1) initial tethering by selectins, (2) activation by cytokines, (3) arrest by integrins, (4) diapedesis or transmigration using matrix remodelers, and (5) extravascular migration toward chemokine gradients. We then review the various strategies that have been investigated for improving MSC homing, including genetic modification, cell surface engineering, in vitro priming of MSCs, and in particular, ultrasound techniques, which have recently gained significant interest. Contextualizing these strategies within the multistep homing model emphasizes that our ability to optimize this process hinges on our understanding of its molecular mechanisms. Moving forward, it is only with a combined effort of basic biology and translational work that the potential of MSC-based therapies can be realized.

  View details for DOI 10.1016/j.isci.2019.05.004

  View details for PubMedID 31121468

• Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability NATURE COMMUNICATIONS Celia-Terrassa, T., Bastian, C., Liu, D., Ell, B., Aiello, N. M., Wei, Y., Zamalloa, J., Blanco, A. M., Hang, X., Kunisky, D., Li, W., Williams, E. D., Rabitz, H., Kang, Y. 2018; 9: 5005

  Abstract

  Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-β-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.

  View details for DOI 10.1038/s41467-018-07538-7

  View details for Web of Science ID 000451310400010

  View details for PubMedID 30479345

  View details for PubMedCentralID PMC6258667

• Ets2 anchors the prometastatic function of mutant p53 in osteosarcoma. Genes & development Liu, D. D., Kang, Y. 2017; 31 (18): 1823-1824

  Abstract

  Mutations in the tumor suppressor p53 occur in a majority of human cancers. Some gain-of-function (GOF) p53 mutations endow tumor cells with increased metastatic ability, although our understanding of the underlying mechanism remains incomplete. In this issue of Genes & Development, Pourebrahim and colleagues (pp. 1847-1857) develop a new mouse model of osteosarcoma in which a GOF mutant p53 allele is expressed specifically in osteoblasts, while the tumor microenvironment remains wild type for p53, allowing for the study of cell-autonomous functions. In this model, the role of GOF mutant p53 in promoting lung metastasis is shown to be critically dependent on the transcription factor Ets2 and is accompanied by the elevated expression of a cluster of small nucleolar RNAs (snoRNAs).

  View details for DOI 10.1101/gad.307439.117

  View details for PubMedID 29051386

  View details for PubMedCentralID PMC5695082

• Identification of Nidogen 1 as a lung metastasis protein through secretome analysis. Genes & development Alečković, M., Wei, Y., LeRoy, G., Sidoli, S., Liu, D. D., Garcia, B. A., Kang, Y. 2017; 31 (14): 1439-1455

  Abstract

  Secreted proteins play crucial roles in mediating tumor-stroma interactions during metastasis of cancer to different target organs. To comprehensively profile secreted proteins involved in lung metastasis, we applied quantitative mass spectrometry-based proteomics and identified 392 breast cancer-derived and 302 melanoma-derived proteins secreted from highly lung metastatic cells. The cancer-specific lung metastasis secretome signatures (LMSSs) displayed significant prognostic value in multiple cancer clinical data sets. Moreover, we observed a significant overlap of enriched pathways between the LMSSs of breast cancer and melanoma despite an overall small overlap of specific proteins, suggesting that common biological processes are executed by different proteins to enable the two cancer types to metastasize to the lung. Among the novel candidate lung metastasis proteins, Nidogen 1 (NID1) was confirmed to promote lung metastasis of breast cancer and melanoma, and its expression is correlated with poor clinical outcomes. In vitro functional analysis further revealed multiple prometastatic functions of NID1, including enhancing cancer cell migration and invasion, promoting adhesion to the endothelium and disrupting its integrity, and improving vascular tube formation capacity. As a secreted prometastatic protein, NID1 may be developed as a new biomarker for disease progression and therapeutic target in breast cancer and melanoma.

  View details for DOI 10.1101/gad.301937.117

  View details for PubMedID 28827399

  View details for PubMedCentralID PMC5588926

• Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis NATURE CELL BIOLOGY Celia-Terrassa, T., Liu, D. D., Choudhury, A., Hang, X., Wei, Y., Zamalloa, J., Alfaro-Aco, R., Chakrabarti, R., Jiang, Y., Koh, B., Smith, H. A., DeCoste, C., Li, J., Shao, Z., Kang, Y. 2017; 19 (6): 711-+

  Abstract

  Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER- breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.

  View details for DOI 10.1038/ncb3533

  View details for Web of Science ID 000402525200018

  View details for PubMedID 28530657

  View details for PubMedCentralID PMC5481166