| | |
Alanna Ruddell, Ph.D.
Research Associate Professor
Department of Comparative Medicine
School of Medicine
University of Washington
Alanna Ruddell obtained her PhD in Developmental Genetics and Anatomy from Case Western Reserve University. She identified genes regulating position effect variegation and retroviral transcription in postdoctoral fellowships at the University of British Columbia and Fred Hutchinson Cancer Research Center. At the University of Rochester Department of Microbiology and Immunology she identified the mechanism of resistance to c-myc-induced lymphomas, and then at Fred Hutchinson Cancer Research Center she discovered B cell-dependent alterations in tumor-draining lymph nodes that promote metastasis. She joined the Department of Comparative Medicine in 2012, and continues her investigations of lymphatic/immune system interactions in tumor growth and metastasis.
Lymph node alterations and metastasis
Cancer cell detection in tumor-draining lymph nodes (TDLNs) is used clinically to diagnose metastasis of many types of human cancers, suggesting that the lymphatic pathway is a common initial route of tumor spread. Immunocompetent mouse models show modest growth of tumor lymphatic vessels (lymphangiogenesis). However, extensive lymphatic sinus growth arises in tumor-draining lymph nodes (TDLNs), even before metastasis is initiated. This is associated with increased lymph drainage, suggesting the hypothesis that TDLN lymphatic sinus growth and accelerated lymph flow actively drive tumor dissemination into draining lymph nodes.
Abnormal accumulation of B cells throughout TDLNs is required to promote lymphatic alterations and metastasis, as B cell-deficient mice with melanoma do not develop TDLN lymphangiogenesis, increased lymph flow, or metastasis. Conversely, preneoplastic E- m -c-myc transgenic mice that feature pre-existing LN B cell accumulation, lymphangiogenesis, and increased lymph flow show accelerated tumor metastasis to TDLNs, demonstrating that TDLN alterations actively promote tumor dissemination via the lymphatics. Mice bearing benign tumors do not develop these TDLN alterations, supporting the idea that TDLN B cells regulate metastatic potential. The involvement of TDLN B cells and lymphatic alterations in metastasis is a major area of interest.
Lymphography imaging for cancer diagnosis
Non-invasive imaging tests could improve diagnosis of cancer metastasis, to identify those patients needing aggressive intervention. Mouse cancer models identified abnormal and increased TDLN lymph flow as diagnostic features in mice developing metastatic tumors. MRI and optical imaging assays are being used to characterize the mechanism by which tumors increase lymph drainage, and to develop diagnostic imaging tests.
Leukocyte and lymphatic endothelium interactions
The lymphatic circulation drains fluid and cells from the periphery through LNs, facilitating immune responses to lymph-borne antigens. A 10.1.1 monoclonal antibody to a lymphatic endothelial surface antigen was developed as a specific reagent for murine lymphatic vessel detection. The 10.1.1 antigen encodes the mCLCA1 protein, which demonstrates strong affinity for the LFA-1 and Mac-1 adhesion molecules expressed on lymphocytes and leukocytes. Investigation of mCLCA1 contributions to leukocyte trafficking and to the immune response should provide new insights to lymphatic/immune system cross-talk.
Current Lab Personnel:
Ruddell, A., Harrell, M.I., Furuya, M., Kirschbaum, S.B., and Iritani, B.M. (2011) B lymphocytes promote lymphogenous metastasis of lymphoma and melanoma. Neoplasia 13:784-757. PMID: 21847366; PMCID: 3156665.
Furuya, M., Kirschbaum, S.B., Paulovich, A., Pauli, B.U., Zhang, H., Alexander, S.J., Farr, A., and Ruddell, A. (2010) Lymphatic endothelial murine chloride channel calcium-activated 1 is a ligand for leukocyte LFA-1 and Mac-1. J. Immunology 185:5769-5777. PMID:20937843; PMCID:3367505.
Ruddell, A., Kelly-Spratt, K., Furuya, M., Parghi, S.S., and Kemp, C.J. (2008) p19/Arf and p53 suppress sentinel lymph node lymphangogenesis and carcinoma metastasis. Oncogene, 27:3145-3155. PMID:18059331.
Ruddell, A., Harrell, M.I., White, S.W., Maravilla, K.R., Iritani, B.M., Minoshima, S., and Partridge, S.C. (2008) Dynamic contrast-enhanced magnetic resonance imaging of tumor-induced lymph drainage. Neoplasia, 10:706-713. PMID:1852009; PMCID:2435006.
Harrell, M.I., Iritani, B.M., and Ruddell, A. (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. American Journal of Pathology 170:774-786. PMID:17255343;1851877.
Ruddell, A., Mezquita, P., Brandvold, K.A., Farr, A., Iritani, B.M. (2003) B lymphocyte-specific expression of c-myc stimulates early and functional expansion of vasculature and lymphatics in hematopoietic tissues. American Journal of Pathology 163:2233-2244. PMID:14633598; PMCID:1892400