Perelman School of Medicine at the University of Pennsylvania

Research

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. The ultimate objective of our research is to develop new, efficient therapies against GBM and other malignant tumors by targeting the cancer microenvironment. 

Vascular transformation

Aberrant vascularization is a hallmark of cancer progression and therapy resistance. However, current anti-vascular treatments that mainly target angiogenic factors, albeit initially groundbreaking, have encountered difficulties and failure in most types of malignant tumors. Our recent studies reveal that tumor-associated endothelial cells exhibit robust plasticity, acquiring mesenchymal phenotypes to induce vascular abnormality (Huang et al, JCI 2016), which suggests endothelial de-transformation as a novel anti-cancer therapeutic strategy. We aim to decipher the key mechanisms that control cell plasticity-driven metabolic, epigenetic, and genetic reprogramming in tumor-associated endothelial cells, which serve as the targets for next-generation anti-vascular therapies. We expect these new vasculotherapies may recondition the tissue microenvironment, block cancer progression, and overcome tumor therapeutic resistance.

Immune microenvironment

Immunotherapy holds great promise for cancer treatment. However, current immunotherapy of solid tumors, primarily by targeting tumor-associated T cells, remains a big challenge, largely due to insufficient infiltration and activation of T cells in the tumors. Our studies aim at elucidating the immunosuppressive mechanisms, by which tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) inhibit infiltration and activation of T cells and NK cells in the tumor microenvironment. We hope to develop new cancer immunotherapies by breaking microenvironment-specific immune suppression, which boosts host-tumor immunity and strengthens adoptive cellular therapy.

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. 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 new 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.

Radiation biology

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. Early studies suggest proton radiation only generates a 10% higher relative biological effectiveness (RBE) than photon radiation. 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 including GSCs (Mitteer et al, Sci Rep 2015). The objectives of our laboratory are to elucidate the underlying mechanisms for proton radiation-induced DNA damage and cell injury, and to develop new proton therapies by optimization of dose fractionation and spatial distribution based on mathematic simulation of the radiation responses.