Description of Research Expertise
Research Interests: Brain tumor; Angiogenesis; Tissue repar; Immunotherapy; Cancer stem cells; Proton radiation.

We work on cancer and regenerative medicine. As a prominent example of malignant solid tumors, glioblastoma (GBM) is among the most deadly human malignancies, largely due to its high resistance to standard therapies. The ultimate objective of our research is to develop efficient therapies against diseases by targeting the tissue microenvironment. We aim to reprogram the microenvironment to block cancer progression, activate anti-tumor immunity, and fuel post-injury tissue repair.

Vascular transformation
Aberrant vascularization is a hallmark of cancer and cardiovascular diseases. However, current anti- and pro- vascular therapies that primarily target angiogenic factors, albeit initially groundbreaking, have encountered major difficulties and failures in treating most cancers and ischemic heart diseases, respectively. We propose that endothelial transformation alternatively drives vessel abnormalities and vascular microenvironment-mediated pathogenesis. Our work reveals that tumor-associated endothelial cells undergo mesenchymal transformation, driving aberrant vascularization and therapeutic resistance (Huang et al, JCI 2016). We uncover that endothelial transformation downregulates VEGFR2 expression, rendering tumor resistance to anti-VEGF treatment (Liu et al, Nature Comm 2018), and that endothelial transformation induces vascular niche-mediated chemoresistance (Huang et al, Science Transl Med 2020). Based on these studies, we propose a new therapeutic concept, namely, “vascular de-transformation” as a next-generation strategy against cancer (Fan, Trends in Cancer 2019).

Immunotherapy
Immunotherapy holds great promise for cancer treatment. However, current immunotherapy of solid tumors remains a big challenge, largely due to the immunosuppressive microenvironment that inhibits T cell infiltration and activation. We are particularly interested in reversal of immune suppression by reprogramming the tumor microenvironment. Our work reveals that vascular niche-derived IL-6 induces alternative macrophage polarization and tumor immunosuppression in GBM (Wang et al, Nature Comm 2018; Yang et al, manuscript in revision). By using whole genome/kinome-wide functional screen approaches, we identified several drivers that modulate T cell infiltration across tumor vasculature, serving as potential targets to improve CAR T immunotherapy (Ma et al, manuscript in revision). The overall goal of our study in this area is to lay the groundwork for the development of microenvironment-targeted treatments, which are expected to activate pro-tumor immunity and to overcome cancer resistance to immune checkpoint blockade and CAR T immunotherapy in solid tumors. We are also interested in deciphering the role of immune microenvironment in tissue repair and are dedicated to develop new immunotherapy for promoting tissue repair.

Cancer stem cells
Cancer stem cells, also known as tumor-initiating cells or tumor-propagating cells, are highly tumorigenic and therapy resistant, which are able to repopulate a tumor after treatment. We are interested in cancer stem cell-mediated tumor resistance to chemotherapy and radiation, emphasizing the mechanisms that control DNA repair and telomere function. We identify that dynamic DNA-PK activation after radiation induces genomic instability in glioma stem cells, leading to therapy resistance (Wang et al, JCI Insight 2018). We reveal a Wnt-mediated mechanism that drives therapy resistance in circulating glioma cells (Liu et al, Cancer Res 2018). In addition, we show that proton radiation exhibits more therapeutic efficacy against glioma stem cells than photon radiation (Mitteer et al, Sci Rep 2015). The goal of our work here is to develop new therapies that specifically eradicate cancer stem cells to overcome therapy resistance and prevent cancer relapse.