Academic Appointments

All Publications

  • Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC. Nature immunology Baer, J. M., Zuo, C., Kang, L., de la Lastra, A. A., Borcherding, N. C., Knolhoff, B. L., Bogner, S. J., Zhu, Y., Yang, L., Laurent, J., Lewis, M. A., Zhang, N., Kim, K., Fields, R. C., Yokoyama, W. M., Mills, J. C., Ding, L., Randolph, G. J., DeNardo, D. G. 2023


    Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.

    View details for DOI 10.1038/s41590-023-01579-x

    View details for PubMedID 37563309

  • An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression. Nature communications Dinh, T. T., Xiang, M., Rajaraman, A., Wang, Y., Salazar, N., Zhu, Y., Roper, W., Rhee, S., Brulois, K., O'Hara, E., Kiefel, H., Dinh, T. M., Bi, Y., Gonzalez, D., Bao, E. P., Red-Horse, K., Balogh, P., Gabris, F., Gaszner, B., Berta, G., Pan, J., Butcher, E. C. 2022; 13 (1): 7448


    Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription. The Madcam1 element also integrates repressive signals from arterial/capillary Notch effectors. Pan-endothelial COUP-TFII overexpression induces ectopic addressin expression in NKX2-3+ capillaries, while NKX2-3 deficiency abrogates expression by HEV. Phylogenetically conserved NCCE are enriched in genes involved in neuron migration and morphogenesis of the heart, kidney, pancreas and other organs. Our results define an NKX-COUP-TFII morphogenetic code that targets expression of mucosal vascular addressins.

    View details for DOI 10.1038/s41467-022-34991-2

    View details for PubMedID 36460642

  • Modulation of Nr2f2 reprograms tumor blood vessels to enhance anti-tumor immunity and immunotherapy. Zhu, Y., Lazarus, N., Brulois, K., Salazar, N., Dinh, T., Pan, J., Butcher, E. AMER ASSOC CANCER RESEARCH. 2021
  • Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression. Immunity Zhu, Y., Herndon, J. M., Sojka, D. K., Kim, K. W., Knolhoff, B. L., Zuo, C., Cullinan, D. R., Luo, J., Bearden, A. R., Lavine, K. J., Yokoyama, W. M., Hawkins, W. G., Fields, R. C., Randolph, G. J., DeNardo, D. G. 2017; 47 (2): 323-338.e6


    Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment.

    View details for DOI 10.1016/j.immuni.2017.07.014

    View details for PubMedID 28813661

    View details for PubMedCentralID PMC5578409

  • Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy NATURE MEDICINE Jiang, H., Hegde, S., Knolhoff, B. L., Zhu, Y., Herndon, J. M., Meyer, M. A., Nywening, T. M., Hawkins, W. G., Shapiro, I. M., Weaver, D. T., Pachter, J. A., Wang-Gillam, A., DeNardo, D. G. 2016; 22 (8): 851-?


    Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

    View details for DOI 10.1038/nm.4123

    View details for Web of Science ID 000381000200010

    View details for PubMedID 27376576

    View details for PubMedCentralID PMC4935930

  • Regramming myeloid responses to improve cancer immunotherapy ONCOIMMUNOLOGY Zhu, Y., Hawkins, W. G., DeNardo, D. G. 2015; 4 (6)


    Infiltration by immunosuppressive myeloid cells helps tumors to overcome immune surveillance and can render patients less responsive to therapeutic intervention. Several recent studies have demonstrated that reprogramming myeloid responses can effectively enhance cancer immunotherapy, suggesting several new potential combination therapies for clinical testing.

    View details for DOI 10.4161/2162402X.2014.974399

    View details for Web of Science ID 000355203300002

    View details for PubMedID 26155432

    View details for PubMedCentralID PMC4492504

  • CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models CANCER RESEARCH Zhu, Y., Knolhoff, B. L., Meyer, M. A., Nywening, T. M., West, B. L., Luo, J., Wang-Gillam, A., Goedegebuure, S. P., Linehan, D. C., DeNardo, D. G. 2014; 74 (18): 5057-5069


    Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate immune suppression, but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T-cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics.

    View details for DOI 10.1158/0008-5472.CAN-13-3723

    View details for Web of Science ID 000342358300010

    View details for PubMedID 25082815

    View details for PubMedCentralID PMC4182950

  • The Extracellular Domain of Notch2 Increases Its Cell-Surface Abundance and Ligand Responsiveness during Kidney Development DEVELOPMENTAL CELL Liu, Z., Chen, S., Boyle, S., Zhu, Y., Zhang, A., Piwnica-Worms, D. R., Ilagan, M. X., Kopan, R. 2013; 25 (6): 585-598


    Notch2, but not Notch1, plays indispensable roles in kidney organogenesis, and Notch2 haploinsufficiency is associated with Alagille syndrome. We proposed that proximal nephron fates are regulated by a threshold that requires nearly all available free Notch intracellular domains (NICDs) but could not identify the mechanism that explains why Notch2 (N2) is more important than Notch1 (N1). By generating mice that swap their ICDs, we establish that the overall protein concentration, expression domain, or ICD amino acid composition does not account for the differential requirement of these receptors. Instead, we find that the N2 extracellular domain (NECD) increases Notch protein localization to the cell surface during kidney development and is cleaved more efficiently upon ligand binding. This context-specific asymmetry in NICD release efficiency is further enhanced by Fringe. Our results indicate that an elevated N1 surface level could compensate for the loss of N2 signal in specific cell contexts.

    View details for DOI 10.1016/j.devcel.2013.05.022

    View details for Web of Science ID 000321483000007

    View details for PubMedID 23806616

    View details for PubMedCentralID PMC3710456

  • Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses CANCER RESEARCH Mitchem, J. B., Brennan, D. J., Knolhoff, B. L., Belt, B. A., Zhu, Y., Sanford, D. E., Belaygorod, L., Carpenter, D., Collins, L., Piwnica-Worms, D., Hewitt, S., Udupi, G. M., Gallagher, W. M., Wegner, C., West, B. L., Wang-Gillam, A., Goedegebuure, P., Linehan, D. C., DeNardo, D. G. 2013; 73 (3): 1128-1141


    Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence seems to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8(+) T lymphocytes. Together, our findings show how targeting TAMs can effectively overcome therapeutic resistance mediated by TICs.

    View details for DOI 10.1158/0008-5472.CAN-12-2731

    View details for Web of Science ID 000315028300011

    View details for PubMedID 23221383

    View details for PubMedCentralID PMC3563931