Endothelial cells, cancer stem cells, angiogenesis, cell plasticity, macrophage transition, brain tumor, and lung cancer.
Vascular niche, cancer stem cells, tumor immunity, and tissue repair.
Vascular transformation & cell plasticity
Aberrant vascularization is a hallmark of cancer progression and therapy resistance. Most highly malignant, solid tumors are characterized by overgrown, topologically and structurally abnormal blood vessels that create a tissue-specific microenvironment by inducing heterogeneous hypoxia and secreting pathogenic factors. However, current anti-vascular treatments that mainly target angiogenic factors have encountered difficulties and failure in most types of highly malignant tumors at different levels. The objective of our laboratory is to develop new anti-vascular therapies by targeting intrinsic aberrations in vascular cells. We aim to decipher the key mechanisms that control cell plasticity-driven metabolic and genetic reprogramming in tumor-associated vasculature, which may lead to discovery of next-generation targets for anti-cancer therapies.
Cancer stem cells
Cancer stem cells, also known as tumor-initiating cells or tumor-propagating cells, are highly tumorigenic and able to differentiate asymmetrically to orchestrate a heterogeneous tumor mass; importantly, cancer stem cells are resistant to chemotherapy and radiation, and therefore contribute significantly to tumor resistance and relapse. Glioblastoma (GBM, grade IV glioma) is the most common and most aggressive primary brain tumor in humans. GBM is among the most lethal of human malignancies with a median survival of approximately 14 months, largely due to its high resistance to standard radio- and chemotherapy. Recent studies have identified a prominent population of glioma stem cells (GSCs) in GBM, which are pluripotent and radio-resistant and have the ability to repopulate tumors. The goal of our laboratory is to develop therapies that are effective at eradicating GSCs. We employ various approaches and methods of vertebrate genetics and human genomics to dissect the convergent and divergent regulatory pathways that govern GSC stemness and resistance to chemotherapy and radiation, induced by either intrinsic signals in GSCs or extrinsic mechanisms from niche cells.
Extracellular matrix, soluble factors, and stromal cells including vascular cells, immune cells and fibroblasts constitute the tissue microenvironment that is crucial for post-injury cardiac repair and tumor development and progression. The newly formed vasculature actively interacts with other microenvironment components, creating a niche conducive to the aberrant functions in tumor cells and ischemic cardiomyocytes. Our studies aim at elucidating the cell-cell interaction mechanisms with the ultimate goal of providing novel therapeutic strategies for reconditioning the tissue microenvironment. Particularly, we are interested in the interaction between endothelial cells and immune cells including macrophages and T cells, which protects the tumor from host immune response. We hope to develop new cancer immunotherapies by breaking vasculature-mediated immune suppression.
Proton therapy is an innovative radiation treatment modality that offers dosimetric advantages over conventional photon (gamma or x-ray) radiation. Proton irradiation deposits dose in small, precise areas with minimal lateral scattering in tissue, ensuring that little radiation is inadvertently delivered to healthy tissue surrounding the tumor. Proton therapy is therefore often the preferred option for treating central nervous malignancies as it minimizes normal tissue damage and neurocognitive deficits. On the other hand, early studies suggest proton radiation only generates a 10% higher relative biological effectiveness (RBE) than photon radiation in many types of cells and tissue. However, more recent studies by us and others indicate that particle radiation including protons exerts significantly greater cytotoxic damage than photon radiation to the radiation-resistant, stem cell-like tumor cells. The objectives of our laboratory are to elucidate the underlying mechanisms with a focus on reactive oxygen species (ROS)-mediated DNA damage and repair, and to develop new proton therapies by optimization of dose fractionation and spatial distribution based on mathematic simulation of the radiation responses.
Huang M, T Liu, Ma P, Mitteer RA, Zhang Z, Kim HJ, Yeo E, Zhang D, Cai P, Li C, Zhang L, Zhao B, Roccograndi L, O’Rourke DM, Dahmane N, Gong Y, Koumenis C, Fan Y.: c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest. 126(5): 1801-14, May 2016.
Zhang Y, He Q, Hu Z, Feng Y, Fan L, Tang Z, Yuan J, Shan W, Li C, Hu X, Tanyi JL, Fan Y, Huang Q, Montone K, Dang CV, Zhang L.: Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat Struct Mol Biol. in press, April 2016.
Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, Zhang Y, Yang L, Shan W, He Q, Fan L, Kandalaft LE, Tanyi JL, Li C, Yuan CX, Zhang D, Yuan H, Hua K, Lu Y, Katsaros D, Huang Q, Montone K, Fan Y, Coukos G, Boyd J, Sood AK, Rebbeck T, Mills GB, Dang CV, Zhang L. : Comprehensive Genomic Characterization of Long Non-coding RNAs across Human Cancers. Cancer Cell 28(4): 529-40, October 2015.
Mitteer RA, Wang YL, Shah J, Gordon S, Fager M, Guardiola-Salmeron C, Carabe-Fernandez A*, and Fan Y*. : Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species. Sci Rep. 5: 13961, September 2015 Notes: *, co-corresponding author.
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Last updated: 09/08/2016
The Trustees of the University of Pennsylvania