Jiayu Jennifer Ye

All Publications

• Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer. Nature communications Lee, S., Ricci, B., Tran, J., Eul, E., Ye, J., Ren, Q., Clever, D., Wang, J., Wong, P., Haas, M. S., Stewart, S. A., Ma, C. X., Fehniger, T. A., Faccio, R. 2025; 16 (1): 1183

  Abstract

  Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.

  View details for DOI 10.1038/s41467-025-56420-w

  View details for PubMedID 39885132

  View details for PubMedCentralID PMC11782527

• Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer CANCER DISCOVERY Belle, J. I., Sen, D., Baer, J. M., Liu, X., Lander, V. E., Ye, J., Sells, B. E., Knolhoff, B. L., Faiz, A., Kang, L., Qian, G., Fields, R. C., Ding, L., Kim, H., Provenzano, P. P., Stewart, S. A., Denardo, D. G. 2024; 14 (7): 1324-1355

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.

  View details for DOI 10.1158/2159-8290.CD-23-0428

  View details for Web of Science ID 001260926600001

  View details for PubMedID 38683144

  View details for PubMedCentralID PMC12155422

• Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression CANCER DISCOVERY Ye, J., Baer, J. M., Faget, D. V., Morikis, V. A., Ren, Q., Melam, A., Delgado, A., Luo, X., Bagchi, S., Belle, J. I., Campos, E., Friedman, M., Veis, D. J., Knudsen, E. S., Witkiewicz, A. K., Powers, S., Longmore, G. D., DeNardo, D. G., Stewart, S. A. 2024; 14 (7): 1302-1323

  Abstract

  The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.

  View details for DOI 10.1158/2159-8290.CD-23-0426

  View details for Web of Science ID 001260926600014

  View details for PubMedID 38683161

  View details for PubMedCentralID PMC11216870

• Cancer-associated fibroblast-derived Dickkopf-1 suppresses NK cell cytotoxicity in breast cancer. Research square Faccio, R., Lee, S., Ricci, B., Tran, J., Ye, J., Clever, D., Eul, E., Wang, J., Wong, P., Ma, C., Fehniger, T. 2024

  Abstract

  Breast cancer is poorly immunogenic, hence able to evade T cell recognition and respond poorly to immune checkpoint blockade. Breast cancer cells can also evade NK cell-mediated immune surveillance, but the mechanism remains enigmatic. Dickkopf-1 (DKK1) is a Wnt/b-catenin inhibitor, whose levels are increased in breast cancer patients and correlate with reduced overall survival. DKK1 is expressed by cancer-associated fibroblasts (CAFs) in orthotopic breast tumors and patient samples, and at higher levels by bone cells. While bone-derived DKK1 contributes to the systemic elevation of DKK1 in tumor-bearing mice, CAFs represent the primary source of DKK1 at the tumor site. Systemic or bone-specific DKK1 targeting reduces primary tumor growth. Intriguingly, specific deletion of CAF-derived DKK1 also limits breast cancer progression, regardless of its elevated levels in circulation and in the bone. DKK1 does not support tumor proliferation directly but rather suppresses the activation and tumoricidal activity of NK cells. Importantly, increased DKK1 levels and reduced number of cytotoxic NK cells are detected in breast cancer patients with progressive bone metastases compared to those with stable disease. Our findings indicate that DKK1 creates a tumor-supporting environment through the suppression of NK cells in breast cancer.

  View details for DOI 10.21203/rs.3.rs-4202878/v1

  View details for PubMedID 38659818

  View details for PubMedCentralID PMC11042392

• Senescent cells promote breast cancer tumorigenesis Ye, J., Delgado, A., Ren, Q., Powers, R. S., Stewart, S. A. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-85

  View details for Web of Science ID 001008193600119

• A Cdh3-b-catenin-laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration DEVELOPMENTAL CELL Hwang, P. Y., Mathur, J., Cao, Y., Almeida, J., Ye, J., Morikis, V., Cornish, D., Clarke, M., Stewart, S. A., Pathak, A., Longmore, G. D. 2023; 58 (1): 34-+

  Abstract

  Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration.

  View details for DOI 10.1016/j.devcel.2022.12.005

  View details for Web of Science ID 000925070800001

  View details for PubMedID 36626870

  View details for PubMedCentralID PMC10010282

• Genotype and Phenotype of Caffeine Metabolism: A Biochemistry Laboratory Experiment JOURNAL OF CHEMICAL EDUCATION Millard, J. T., Passang, T., Ye, J., Kline, G. M., Beachy, T. M., Hepburn, V. L., Klinkerch, E. J. 2018; 95 (10): 1856-1860

  View details for DOI 10.1021/acs.jchemed.8b00318

  View details for Web of Science ID 000447816500023

• The Influence of <i>CYP1A2</i> Genotype on Caffeine Consumption Habits and Athletic Performance Enhancement in Collegiate Distance Runners Ye, J., Nagy, E., Millard, J. T. FEDERATION AMER SOC EXP BIOL. 2017

  View details for Web of Science ID 000405986503434