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Prof Dr. Jonathan P. Sleeman

It is rare for a cancer patient to die from the effects of their initial tumor, and the metastatic spread of tumor cells that is ultimately responsible for the vast majority of cancer deaths. Understanding the cell and molecular biology of invasion and metastasis and the genetic changes that drive these processes represents one of the last great frontiers of exploratory cancer research.

Therapies directed against metastatic cells hold the promise of clearing the body of tumor cells and curing the patient. The global aim of our work is to understand tumor metastasis at the cellular and molecular levels, and to apply this and other knowledge to the treatment of human cancer. One focus of our research in this area is to understand the degree to which the dissemination of tumor cells via the lymphatic system contributes to metastasis formation in vital organs.

Major research questions include:

  • How do primary tumors interact with and regulate the local lymphatic microvasculature during metastatic progression?
  • Do regional and local effects of pro-lymphangiogenic growth factors have effects beyond the primary tumor that contribute to metastasis formation?
  • What is the relative importance to metastasis formation of dissemination via the lymphatic system compared to dissemination via the blood circulatory system?
  • What genetic changes in tumor cells promote dissemination via the lymphatic system?
  • Do novel therapies that inhibit tumor-induced lymphangiogenesis have potential clinical application for suppressing metastasis and increasing patient survival?
Lymphatic drainage from the flank skin in the presence of an experimental breast tumor. MT-450 breast cancer cells were implanted into the no. 4 mammary fat pad of w/Fu rats. Tumors were allowed to grow for 18 days, then the rats were intradermally injected with Evans blue dye at the level of the lower rib cage on the flank laterally from the midline. The rats were sacrificed 2 hours later, and the skin, tumor and mammary glands were separated from the underlying muscle layer to expose the lymphatic drainage and lymph nodes. A. Complete field of view showing the primary tumor (PT) in the mammary gland, and the lymphatic vessels (LV) that drain from the tumor to the axillary node (LN). The intradermal injection site downstream of the tumor is the large intense blue area. Block boxes indicate areas shown at higher magnification in B-D. B. Axillary node. C. Draining lymphatic vessels. D. Primary tumor. From Quagliata et al., Clin Exp Metastasis, 31: 351-65, 2014.

Project-related publications

  1. Thiele W, Rothley M, Schmaus A, Plaumann D, Sleeman JP. Flow cytometry-based isolation of lymphatic endothelial cells from newborn rats. Lymphology, 47: 177-186, 2014.
  2. Quagliata L, Klusmeier S, Cremers N, Pytowski B, Harvey A, Pettis R, Thiele W, Sleeman JP. Lymph node lymphangiogensis is required for lymph node but not lung metastasis formation in a syngeneic rat breast cancer model. Clin Exp Metastasis, 31: 351-65, 2014.
  3. Schmaus A, Rothley M, Dimmler A, Sipos B, Faller G, Thiele W, Allgayer A, Hohenberger P, Post S, Sleeman JP. Quantification of hyaluronan degradation products in tumor interstitial fluid. British J. Cancer, 111: 559-567, 2014.
  4. Thiele W, Rothley M, Teller N, Jung N, Bulat B, Plaumann D, Vanderheiden S, Schmaus A, Cremers C, Göppert B, Dimmler A, Eschbach V, Quagliata L, Thaler S, Marko D, Bräse S, Sleeman JP. Delphinidin is a novel inhibitor of lymphangiogenesis, but promotes mammary tumor growth and metastasis formation in syngeneic experimental rats. Carcinogenesis, 34: 2804-13, 2013.
  5. Thiele W, Krishnan J, Rothley M, Weih D, Plaumann D, Kuch V, Quagliata L, Weich H, Sleeman JP. VEGFR-3 is expressed on megakaryocyte precursors in the murine bone marrow and plays a regulatory role in megakaryopoiesis. Blood, 120: 1899-1907, 2012.
  6. Neeb A, Wallbaum S, Novac N, Scholl I, Dukovic-Schulze S, Schreiber C, Schlag P, Moll J, Stein U, Sleeman, JP. The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal carcinoma patients. Oncogene, 31: 3796-3806, 2012.
  7. Thiele W, Novac N, Mink S, Schreiber C, Plaumann D, Fritzmann J, Schwager C, Regiert T, Huber PE, Stein U, Schlag P, Moll J, Abdollahi A, Sleeman JP . Discovery of a novel tumor metastasis-promoting gene NVM-1. J. Pathol., 225: 96-105, 2011.
  8. Müller T, Stein U, Poletti A, Garzia L, Rothley M, Plaumann D, Thiele W, Bauer M, Galasso A, Schlag P, Pankratz M, Zollo M, Sleeman JP. ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients. Oncogene 29: 2393 – 2403, 2010.
  9. Rothley M, Thiele W, Schacht V, Plaumann D, Gartner M, Giannis A, Sleeman JP . Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor-induced lymphangiogenesis in vivo. Int. J. Cancer 125: 34 – 42, 2009.
  10. Bruyère F, Melen-Lamalle L, Blacher S, Roland G, Thiry M, Moons L, Frankenne F, Carmeliet P, Alitalo K, Libert C, Sleeman JP, Foidart JM, Noël A. Modeling lymphangiogenesis in a three-dimensional culture system. Nat Methods 5: 431-437, 2008.

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