|Human tumor cells (red) grow and induce a vascular supply (green) in live, optically transparent zebrafish.|
Our major research objective is to understand how human cancer develops and spreads through the body's circulation (cell metastasis) and to use this information to design novel immune therapies and pharmaceuticals to eradicate primary and secondary metastatic tumors.
Cancer is a highly lethal disease because invasive metastatic cancer cells leave the primary tumor site and enter the circulation leading to systemic dissemination. These metastatic cancer cells then migrate out of the circulation and colonize vital organs like the liver, lungs, and brain where they disrupt normal physiological functions leading to patient death. Cell metastasis remains the major leading cause of death in cancer patients. In fact, approximately 8.2 million people will die from cancer worldwide this year due to metastatic complications. Thus, there is an urgent need to develop new therapeutics and treatment strategies that target the primary tumor and rid the body of metastatic cells. The Development of such treatments would sever the "Achilles' heel" of cancer, saving countless lives, which is the primary goal of our laboratory. To achieve this goal our laboratory works closely with numerous academic and corporate researchers worldwide.
Recent work in the Klemke laboratory has unlocked new insights and concepts that explain how tumors form and metastatic cancer cells migrate and invade the body. Our pioneering work is also leading the charge to develop novel immune therapies, small molecule compounds, and adoptive immune cells treatments to combat tumor formation, angiogenesis,and cell metastasis as outlined below.
|Time-lapse video of a human cancer cell (red) migrating along the inner vessel surface (green) in live, optically transparent zebrafish.|
Transparent animals open the window to view tumor formation, angiogenesis, and metastasis: Our laboratory pioneered the use of unique animal models to visualize how metastatic tumor cells and immune cells move through blood vessels, tissues, and various organs of the body. The unprecedented nature of his work takes advantage of the fact that, unlike humans and other mammals, chicken and zebrafish tissues are relatively transparent. This amazing feature provides a clear window to view tumor cell movement and blood vessel formation/remodeling and immune cell trafficking in the body with incredible clarity and resolution using standard confocal microscopy. These animal models are also highly amenable to therapeutic treatment, making them ideal for evaluating anti-metastatic/angiogenic agents and unraveling their specific mode of action in vivo. This powerful approach has provided new insight into how experimental therapeutics and adoptive immune therapies attack the primary tumor, inhibit new vessel growth, and target cell metastasis. Learn More
|Upper picture is a confocal image in the z plane of a green fluorescent cell protruding invadopodia membranes through the microporus filter (not visible). Lower picture is a cell protruding its invadopodia through a 3.0 um pore to the lower surface. Invadopodia are stained with rodamine-phalloidin to visualize the f-actin cytoskeleton.|
'Fingerprinting' metastatic culprits: Dr. Klemke's research program employs unique proteomic, phosphoproteomic, genomic and bioinformatics methodologies to identify novel phosphoprotein/kinase biomarkers (fingerprints) and map global kinase signaling networks that control cell polarization, immune cell homing, cell migration, proliferation, drug resistance, and cancer cell metastasis. To obtain the 'fingerprint' of metastatic cells, our lab has pioneered the development of important new subcellular membrane purification methods using microporous filters to uncover thousands of unique protein and gene signatures, which drive the metastatic behavior of cancer and immune cells. These molecular 'fingerprints' and their annotated signaling networks are being used as biomarkers to detect metastatic cells in the body and to evaluate the efficacy of novel anti-tumor and anti-metastatic agents using preclinical animal models of cancer. Learn More
|Genetic knockdown of PEAK1 tyrosine kinase (shPEAK1) increases sensitivity to the chemotherapeutic agent gemcitabine in gemcitabine resistant human pancreatic cancer cells. Control cells treated with random shRNA (shCntrl). IC50 = half maximal inhibitory concentration. RFU = relative fluorescent units.|
Cancer Therapeutics, Chemoresistance, and Immune Oncology: Mechanistic insights provided by our experiments have led to the design and use of novel therapeutics that target the primary tumor, tumor-induced angiogenic vessels, and metastatic disease. In collaboration with leading medicinal and natural compound chemists at UCSD and in the corporate sector, our laboratory is characterizing new small molecule compounds, phytochemicals, and immune cell-based therapeutics (e.g NK, CAR-T Cells, etc.) that target metastatic tumor cells and their life sustaining blood supply. We are also investigating the mechanisms that lead to acquired and innate chemoresistance and have identified important signaling pathways and biomarkers that mediate this process. Several lead compounds, immune cell therapies, and natural treatments (nutraceuticals) have been identified that show promise, which are being developed for evaluation in early stage clinical trials. Learn More