Tumor Microenvironment, Oncoimmunology, Stroma-Targeting Therapeutics
Solid tumor tissue is not only composed of neoplastic epithelial cells, rather, it comprises a range of proliferating stromal cells such as fibroblasts and macrophages. Dr. Huang’s research team has been focusing on the tissue microenvironment reprogramming for cancer development and progression. They have exploited several transgenic and mixed cells-transplanted mouse models to explore the cell-cell interplays in the desmoplastic tumor microenvironment. Desmoplasia is a common hallmark of many malignancies including non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC). In a PDAC tissue, desmoplastic stroma generally constitutes 70~90% of total tumor volume and is closely associated with rapid tumor growth, immunosuppression, metastasis, and therapeutic resistance. Dr. Huang’s laboratory is also paying much attention on the therapeutics targeting desmoplastic PDAC stroma.
RESEARCH ACTIVITIES & ACCOMPLISHMENT
Cancer desmoplasia results from the production of a huge amount of extracellular matrix by a remarkable number of myofibroblasts. Myofibroblasts, also known as activated fibroblasts or cancer-associated fibroblasts (CAFs), can be derived from activation of stellate cells or tissue-resident fibroblasts. Additionally, 30~40% of CAFs can arise from the endothelial-to-mesenchymal transition (EndoMT) of endothelial cells. In Dr. Huang’s recently published results, EndoMT-derived CAFs can exhibit a potent tumor-promoting effect by producing extracellular HSP90α (eHSP90α) to foster gaining-of-stemness of colorectal cancer cells. Additionally, a mix of EndoMT-derived CAFs with PDAC cell grafts significantly recruits myeloid-derived macrophages, prevents immune T cells, and promotes the growth of tumor with desmoplasia. EndoMT-derived CAFs can facilitate M2-polarization of tumor-infiltrating macrophages through CD91-TLR4 receptor and MyD88-IRAK complex-associated IKKα/β−NF-κB/IRF3 and JAK2/TYK2−STAT-3 signaling pathways. The M2-polarized macrophages do not only secrete IL-10 and TGF-β to suppress effective and cytotoxic T cells, but also produce VEGF to stimulate tumor angiogenesis. Moreover, these M2-polarized macrophages express and secrete a great amount of eHSP90α and create an eHSP90α-rich tumor microenvironment which has the advantage of cancer cell spreading and gain-of-stemness. In collaborating with the research teams at Institute of Biotechnology and Pharmaceutical Research, Dr. Huang and his colleagues have been developing novel anti-desmoplasia agents and strategies for pancreatic adenocarcinoma therapy.