Ian Guldner

All Publications

• Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish. Nature aging Costa, E. K., Chen, J., Guldner, I. H., Mboning, L., Schmahl, N., Tsenter, A., Nagvekar, R., Wu, M. R., Moran-Losada, P., Bouchard, L. S., Wang, S., Singh, P. P., Pellegrini, M., Brunet, A., Wyss-Coray, T. 2026

  Abstract

  Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA sequencing on 13 tissues at six different ages in male and female African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced 'atlas' dataset revealed varying strength of sex-age interactions across killifish tissues and age-altered genes and biological pathways that are evolutionarily conserved in mice and humans. We discovered a female-biased myeloid shift with age in the killifish hematopoietic organ, developed tissue-specific 'transcriptomic clocks' and identified biomarkers predictive of chronological age. We showed the importance of sex-specific clocks for selected tissues, validated the tissue clocks with an independent transcriptomic dataset and used them to evaluate different lifespan interventions in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.

  View details for DOI 10.1038/s43587-026-01074-6

  View details for PubMedID 41776309

  View details for PubMedCentralID 7059165

• Ageing promotes microglial accumulation of slow-degrading synaptic proteins. Nature Guldner, I. H., Wagner, V. P., Moran-Losada, P., Shi, S. M., Golub, S. W., Hevler, J. F., Chen, K., Meese, B. T., Ghoochani, A., Pulido, E., Oh, H. S., Le Guen, Y., Lu, N., Wong, P. S., To, N. S., Garceau, D., Guo, Z., Luo, J., Bertozzi, C. R., Lundberg, E., Abu-Remaileh, M., Sasner, M., Keller, A., Yang, A. C., Cheung, T. H., Wyss-Coray, T. 2026

  Abstract

  Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

  View details for DOI 10.1038/s41586-025-09987-9

  View details for PubMedID 41565824

  View details for PubMedCentralID 3836174

• Biomarkers. Alzheimer's & dementia : the journal of the Alzheimer's Association Oh, H. S., Urey, D. Y., Karlsson, L., Zhu, Z., Shen, Y., Farinas, A., Timsina, J., Duggan, M. R., Chen, J., Guldner, I. H., Morshed, N., Yang, C., Western, D., Ali, M., Guen, Y. L., Trelle, A. N., Herukka, S., Rauramaa, T., Hiltunen, M., Lipponen, A., Luikku, A. J., Poston, K. L., Mormino, E. C., Wagner, A. D., Wilson, T. N., Channappa, D., Leinonen, V., Stevens, B., Ehrenberg, A. J., Gottesman, R. F., Coresh, J., Walker, K. A., Zetterberg, H., Bennett, D. A., Franzmeier, N., Hansson, O., Cruchaga, C., Wyss-Coray, T. 2025; 21 Suppl 2: e102349

  Abstract

  BACKGROUND: Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous, with symptom onset occurring between ages 40-100 years and conversion from mild cognitive impairment (MCI) to AD dementia occurring in 2-20 years. Biomarkers for amyloid-beta (Abeta) and tau proteins, the hallmark AD pathologies, have improved diagnosis and drug development but explain only 20-40% of the variance in AD-related cognitive impairment (CI).METHOD: To discover additional biomarkers of CI in AD, we perform cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerge as the strongest correlates of CI, independent of Abeta and tau.RESULT: Using machine learning, we derive the CSF YWHAG:NPTX2 synapse protein ratio, which explains 27% of the variance in CI beyond CSF PTau181:Abeta42, 10% beyond tau PET, and 28% beyond CSF NfL, GAP43, and Ng in Abeta- and phosphorylated tau- positive (A+T1+) individuals. We find YWHAG:NPTX2 also increases with normal aging and at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. For prognosis, we define YWHAG:NPTX2 thresholds to stratify A+T1+ individuals into five groups that track with future cognitive resilience versus decline. Most notably, among A+T1+ MCI individuals, those in the predicted cognitively normal group have a 73% reduced risk of cognitive decline, while those in the predicted dementia group have a 2.3 times increased risk, after adjusting for CSF PTau181:Abeta42, CSF NfL, CSF Ng, CSF GAP43, age, APOE4, and sex. Lastly, we develop a plasma proteomic signature of CI, which we evaluate in 13,401 samples, that partly recapitulates CSF YWHAG:NPTX2.CONCLUSION: Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of Abeta, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

  View details for DOI 10.1002/alz70856_102349

  View details for PubMedID 41451464

• Synaptic proteins that aggregate and degrade slower with aging accumulate in microglia. bioRxiv : the preprint server for biology Guldner, I. H., Wagner, V. P., Moran-Losada, P., Shi, S. M., Chen, K., Meese, B. T., Oh, H., Le Guen, Y., Lu, N., Wong, P. S., To, N. S., Garceau, D., Guo, Z., Luo, J., Sasner, M., Keller, A., Yang, A. C., Cheung, T., Wyss-Coray, T. 2025

  Abstract

  Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging1,2. We engineered bioorthogonal tools3 which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia. We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal 'aggregome' encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia. These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

  View details for DOI 10.1101/2025.05.20.654652

  View details for PubMedID 40475609

  View details for PubMedCentralID PMC12139995

• A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase. Nature communications Engel, A., Wagner, V., Hahn, O., Foltz, A. G., Atkins, M., Beganovic, A., Guldner, I. H., Lu, N., Saksena, A., Fischer, U., Ludwig, N., Meese, E., Wyss-Coray, T., Keller, A. 2025; 16 (1): 4588

  Abstract

  An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA expression across the mouse lifespan (7 time points) and two aging interventions. MicroRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and mediate aging speed. We first established sex- and brain-region-specific microRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific microRNA expression changes during aging. We identified three sex-independent brain aging microRNAs (miR-146a-5p, miR-155-5p, and miR-5100). For miR-155-5p, we showed that these expression changes are driven by aging microglia and target mTOR signaling pathway components and other cellular communication pathways. In this work, we identify strong sex-brain-region-specific aging microRNAs and microglial miR-155-5p as a promising therapeutic target.

  View details for DOI 10.1038/s41467-025-59860-6

  View details for PubMedID 40382330

  View details for PubMedCentralID PMC12085673

• A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease. Nature medicine Oh, H. S., Urey, D. Y., Karlsson, L., Zhu, Z., Shen, Y., Farinas, A., Timsina, J., Duggan, M. R., Chen, J., Guldner, I. H., Morshed, N., Yang, C., Western, D., Ali, M., Le Guen, Y., Trelle, A., Herukka, S. K., Rauramaa, T., Hiltunen, M., Lipponen, A., Luikku, A. J., Poston, K. L., Mormino, E., Wagner, A. D., Wilson, E. N., Channappa, D., Leinonen, V., Stevens, B., Ehrenberg, A. J., Gottesman, R. F., Coresh, J., Walker, K. A., Zetterberg, H., Bennett, D. A., Franzmeier, N., Hansson, O., Cruchaga, C., Wyss-Coray, T. 2025

  Abstract

  Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10-4) and A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10-16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.

  View details for DOI 10.1038/s41591-025-03565-2

  View details for PubMedID 40164724

  View details for PubMedCentralID 8574196

• A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase. bioRxiv : the preprint server for biology Engel, A., Wagner, V., Hahn, O., Foltz, A. G., Atkins, M., Beganovic, A., Guldner, I. H., Lu, N., Saksena, A., Fischer, U., Ludwig, N., Meese, E., Wyss-Coray, T., Keller, A. 2025

  Abstract

  An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA (miRNA) expression across the mouse lifespan (7 time points) and two aging interventions composed of 1009 samples. MiRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and are known to mediate aging speed. We first established sex- and brain-region-specific miRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific miRNA expression changes during aging. The corpus callosum in males and the choroid plexus in females exhibited strong sex-specific age-related signatures. In this work, we identified three sex-independent brain aging miRNAs (miR-146a-5p, miR-155-5p and miR-5100). We showed for miR-155-5p that these expression changes are driven by aging microglia. MiR-155-5p targets mTOR signaling pathway components and other cellular communication pathways and is hence a promising therapeutic target.

  View details for DOI 10.1101/2025.03.15.643430

  View details for PubMedID 40161726

  View details for PubMedCentralID PMC11952541

• Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish. bioRxiv : the preprint server for biology Costa, E. K., Chen, J., Guldner, I. H., Mboning, L., Schmahl, N., Tsenter, A., Wu, M., Moran-Losada, P., Bouchard, L. S., Wang, S., Singh, P. P., Pellegrini, M., Brunet, A., Wyss-Coray, T. 2025

  Abstract

  Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA-sequencing on 13 tissues at 6 different ages in the African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced 'atlas' dataset reveals the varying strength of sex-age interactions across killifish tissues and identifies age-altered biological pathways that are evolutionarily conserved. Demonstrating the utility of this resource, we discovered that the killifish head kidney exhibits a myeloid bias during aging, a phenomenon more pronounced in females than in males. In addition, we developed tissue-specific 'transcriptomic clocks' and identified biomarkers predictive of chronological age. We show the importance of sex-specific clocks for selected tissues and use the tissue clocks to evaluate a dietary intervention in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.

  View details for DOI 10.1101/2025.01.28.635350

  View details for PubMedID 39975269

• APOE4/4 is linked to damaging lipid droplets in Alzheimer's diseasemicroglia. Nature Haney, M. S., Palovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C., Tsai, A., Guldner, I. H., Lamichhane, B. S., Smith, A., Schaum, N., Calcuttawala, K., Shin, A., Wang, Y., Wang, C., Koutsodendris, N., Serrano, G. E., Beach, T. G., Reiman, E. M., Glass, C. K., Abu-Remaileh, M., Enejder, A., Huang, Y., Wyss-Coray, T. 2024

  Abstract

  Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Abeta induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

  View details for DOI 10.1038/s41586-024-07185-7

  View details for PubMedID 38480892

• Atlas of the aging mouse brain reveals white matter as vulnerable foci. Cell Hahn, O., Foltz, A. G., Atkins, M., Kedir, B., Moran-Losada, P., Guldner, I. H., Munson, C., Kern, F., Pálovics, R., Lu, N., Zhang, H., Kaur, A., Hull, J., Huguenard, J. R., Grönke, S., Lehallier, B., Partridge, L., Keller, A., Wyss-Coray, T. 2023

  Abstract

  Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.

  View details for DOI 10.1016/j.cell.2023.07.027

  View details for PubMedID 37591239

• A nanotherapeutic approach to selectively eliminate metastatic breast cancer cells by targeting cell surface GRP78. Nanoscale Shin, J., Kim, B., Lager, T. W., Mejia, F., Guldner, I., Conner, C., Zhang, S., Panopoulos, A. D., Bilgicer, B. 2023

  Abstract

  Here, rational engineering of doxorubicin prodrug loaded peptide-targeted liposomal nanoparticles to selectively target metastatic breast cancer cells in vivo is described. Glucose-regulated protein 78 (GRP78), a heat shock protein typically localized in the endoplasmic reticulum in healthy cells, has been identified to home to the cell surface in certain cancers, and thus has emerged as a promising therapeutic target. Recent reports indicated GRP78 to be expressed on the cell surface of an aggressive subpopulation of stem-like breast cancer cells that exhibit metastatic potential. In this study, a targeted nanoparticle formulation with a GRP78-binding peptide (Kd of 7.4 ± 1.0 μM) was optimized to selectively target this subpopulation. In vitro studies with breast cancer cell lines showed the targeted nanoparticle formulation (TNPGRP78pep) achieved enhanced cellular uptake, while maintaining selectivity over the control groups. In vivo, TNPGRP78pep loaded with doxorubicin prodrug was evaluated using a lung metastatic mouse model and demonstrated inhibition of breast cancer cell seeding to lungs down at the level of negative control groups. Combined, this study established that specific-targeting of surface GRP78 expressing a subpopulation of aggressive breast cancer cells was able to inhibit breast cancer metastasis to lungs, and underpinned the significance of GRP78 in breast cancer metastasis.

  View details for DOI 10.1039/d3nr00800b

  View details for PubMedID 37526009

• APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia. bioRxiv : the preprint server for biology Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C., Tsai, A., Guldner, I. H., Lamichhane, B. S., Smith, A., Schaum, N., Calcuttawala, K., Shin, A., Wang, Y. H., Wang, C., Koutsodendris, N., Serrano, G. E., Beach, T. G., Reiman, E. M., Glass, C. K., Abu-Remaileh, M., Enejder, A., Huang, Y., Wyss-Coray, T. 2023

  Abstract

  Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

  View details for DOI 10.1101/2023.07.21.549930

  View details for PubMedID 37546938

  View details for PubMedCentralID PMC10401952

• Activated immune cells drive neurodegeneration NATURE Guldner, I. H., Wyss-Coray, T. 2023; 615 (7953): 588-589

  View details for Web of Science ID 000961443400002

• Activated immune cells drive neurodegeneration in an Alzheimer's model. Nature Guldner, I. H., Wyss-Coray, T. 2023; 615 (7953): 588-589

  View details for DOI 10.1038/d41586-023-00600-5

  View details for PubMedID 36890310

• Isolation of mouse brain-infiltrating leukocytes for single cell profiling of epitopes and transcriptomes. STAR protocols Guldner, I. H., Golomb, S. M., Wang, Q., Wang, E., Zhang, S. 2021; 2 (2): 100537

  Abstract

  High dimensional compositional and transcriptional profiling of heterogeneous brain-infiltrating leukocytes can lead to novel biological and therapeutic discoveries. High-quality single-cell leukocyte preparations are a prerequisite for optimal single cell profiling. Here, we describe a protocol for epitope and RNA-preserving dissociation of adult mouse brains and subsequent leukocyte purification and staining, which is adaptable to homeostatic and pathogenic brains. Leukocyte preparation following this protocol permits exquisite single-cell surface protein and RNA profiling in applications including CyTOF and CITE-seq. For complete details on the use and execution of this protocol, please refer to Guldner etal. (2020) and Golomb etal. (2020).

  View details for DOI 10.1016/j.xpro.2021.100537

  View details for PubMedID 34036283

• Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer NATURE COMMUNICATIONS Wang, Q., Guldner, I. H., Golomb, S. M., Sun, L., Harris, J. A., Lu, X., Zhang, S. 2019; 10: 3817

  Abstract

  Acquired resistance to targeted cancer therapy is a significant clinical challenge. In parallel with clinical trials combining CDK4/6 inhibitors to treat HER2+ breast cancer, we sought to prospectively model tumor evolution in response to this regimen in vivo and identify a clinically actionable strategy to combat drug resistance. Despite a promising initial response, acquired resistance emerges rapidly to the combination of anti-HER2/neu antibody and CDK4/6 inhibitor Palbociclib. Using high-throughput single-cell profiling over the course of treatments, we reveal a distinct immunosuppressive immature myeloid cell (IMC) population to infiltrate the resistant tumors. Guided by single-cell transcriptome analysis, we demonstrate that combination of IMC-targeting tyrosine kinase inhibitor cabozantinib and immune checkpoint blockade enhances anti-tumor immunity, and overcomes the resistance. Furthermore, sequential combinatorial immunotherapy enables a sustained control of the fast-evolving CDK4/6 inhibitor-resistant tumors. Our study demonstrates a translational framework for treating rapidly evolving tumors through preclinical modeling and single-cell analyses.

  View details for DOI 10.1038/s41467-019-11729-1

  View details for Web of Science ID 000482398900019

  View details for PubMedID 31444334

  View details for PubMedCentralID PMC6707314

• Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer NATURE COMMUNICATIONS Ni, Y., Schmidt, K. R., Werner, B. A., Koenig, J. K., Guldner, I. H., Schnepp, P. M., Tan, X., Jiang, L., Host, M., Sun, L., Howe, E. N., Wu, J., Littlepage, L. E., Nakshatri, H., Zhang, S. 2019; 10: 2860

  Abstract

  Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.

  View details for DOI 10.1038/s41467-019-10743-7

  View details for Web of Science ID 000473132200024

  View details for PubMedID 31253784

  View details for PubMedCentralID PMC6599020