We study how tissue microenvironment influence the development and function of mononuclear phagocytes (MP cells) of the innate immune system, which comprises of monocytes, dendritic cells (DC), and macrophages. Dendritic cells excel at antigen presentation to induce adaptive immune responses while tissue-macrophages are versatile cells with roles in innate immunity and tissue homeostasis. Many distinct phenotypic and functional subsets of these cells have been described. Each tissue harbors its own unique repertoire of DC and macrophage subsets, which undergoes significant changes during pathological conditions such as inflammation, infection, tumor, etc. Circulating monocytes can infiltrate tissue and undergo differentiation into either DC or macrophage, but factors that control this decision process is not fully understood. Macrophages can also develop from embryonic precursors, independent of monocytes. Likewise, DCs also develop from bone-marrow derived precursors independent of monocytes. Therefore, MP cells are phenotypically, functionally, and developmentally heterogeneous. We are interested in understanding molecular mechanisms that control this heterogeneity in the steady state as well as in pathological conditions such as cancer.
Project 1: Role of Mononuclear Phagocytes in Solid Tumors
The host immune system is capable of recognizing tumor-associated antigens and mount an anti-tumor immune response, which are prevented by the immunosuppressive tumor microenvironment. Evading immune-detection and suppressing anti-tumor immune responses are part of tumor evolution. One way the tumor achieves this is by recruiting immunosuppressive and tumor promoting MP cells such as M2 macrophages while suppressing cells that can induce and support anti-tumor immune responses such as DCs. We are investigating the distribution, function, and development of these cells in solid tumor microenvironment. The overarching goal is to devise novel therapeutic strategies targeting these tumor-infiltrating MP cells. In the context of tumor subtype, most of our work is focused on sarcomas, a rare but lethal type of solid tumor. We also have a newer project around medulloblastoma, a lethal pediatric cancer. Our approach includes the use of genetically engineered mouse models of sarcoma, transgenic models of myeloid lineage tracing and ablation, patient derived samples, and in vitro cell-based systems.
Figure 1: Genetically engineered mouse model of synovial sarcoma. Synovial sarcomas are associated with a t(X;18) chromosomal translocation, which generates a chimeric SYT-SSX oncogene. Conditional expression of this fusion oncogene in mice induces synovial sarcomas. Expression of the fusion oncogene can be tracked by the expression of the linked GFP reporter.
Figure 2: Genetically engineered mouse mode of medulloblastoma. Aberrant activation of sonic hedgehog signaling in Ptch+/- p53-/- mice generates medulloblastomas. IHC staining with calbindin marks purkinje cells and highlights tumor-induced disruption in the cerebellar architecture.
Selected Relevant Publications
- A Conditional Mouse Model of Synovial Sarcoma: Insights into a Myogenic Origin. Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR. Cancer Cell (2007) (PMID: 17418413)
- A CreER-based Random Induction Strategy for modeling Translocation-associated Sarcomas in Mice. Haldar M, Hedberg ML, Hockin MF, Capecchi MR. Cancer Research (2009) (PMID: 19351831)
- Synovial Sarcoma: From Genetics to Genetic-based Animal Modeling. Haldar M, Randall RL, Hockin MF, Capecchi MR. Clinical Orthopedics and Related Research (PMID: 18563504)
Project 2: Cellular and Molecular Basis of MP Cell Heterogeneity
Circulating monocytes infiltrate tissue where they can differentiate into DCs or macrophages. This decision of a monocyte has profound implication on tissue homeostasis, given the distinct functions of DC and macrophage. However, the cellular and molecular basis of this decision process is poorly understood. Recent work has demonstrated a dichotomy in the differentiation potential of circulating monocytes. While Ly6C+ monocytes were capable of generating both DC and macrophages, Ly6C- monocytes were largely restricted to a macrophage fate. One project in the laboratory explores the molecular, genetic, and epigenetic basis for this distinct differentiation potential of the two monocyte subsets. Another line of investigation in the laboratory relates to the role of the transcription factor SpiC in macrophages. Previous work has demonstrated the requirement of this transcription factor for the development of heme-degrading and iron-recycling macrophages. Importantly, SpiC was itself induced by high levels of heme in the microenvironment. This molecular circuitry ensures the generation of heme-degrading and iron-recycling macrophages in regions with high levels of heme. However, the specific targets of SpiC and the full range of its function in MP cell biology is not well understood, which we are currently investigating.
Figure 3: Heme-induced development of iron-recycling macrophages. Molecular circuitry underlying the development of heme-degrading and iron-recycling macrophages from monocytes in heme-rich environment. Bach1: BTB and CNC homology 1, a transcription factor. SpiC: Spi-1/PU.1 related transcription factor, HO1: Heme oxygenase 1, a heme-degrading enzyme.
Selected Relevant Publications
- Heme-mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages. Haldar M, Kohyama M, So AY, Kc W, Wu X, Briseño CG, Satpathy AT, Kretzer NM, Arase H, Rajasekaran NS, Wang L, Egawa T, Igarashi K, Baltimore D, Murphy TL, Murphy KM. Cell (2014) (PMID: 24630724)
- Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells. Briseño CG*, Haldar M*, Kretzer NM, Wu X, Theisen DJ, Kc W, Durai V, Grajales-Reyes GE, Iwata A, Bagadia P, Murphy TL, Murphy KM (* equal contributions). Cell Reports (2016) (PMID: 27264183)
- Origin, Development, and Homeostasis of Tissue-resident Macrophages. Haldar M, Murphy KM. Immunological Reviews (PMID: 25319325)
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