CCBIO Seminar – Huocong Huang

Speaker: Huocong Huang, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA

Title: Heterogeneity of cancer-associated fibroblasts in pancreatic cancer

Place: digital event as webinar in Zoom, through this link. If asked for a password, use: N4qvm7nn
Note: Please change your username to your name when logging in, so that chair can address you if you have questions.

Time: November 5, 2020 at 14:30 Central European Time (CET), the timezone in Norway

Chair: Jim Lorens

Abstract:

Pancreatic cancer is a lethal disease characterized by extensive desmoplasia caused by the rapid expansion of cancer-associated fibroblasts, resulting in the formation of dense stroma. CAFs stimulate cancer progression by secreting a variety of factors that support cancer cells and facilitate immunosuppression. In addition, they also secrete extracellular matrix that provides survival and invasion cues to cancer cells and impairs drug delivery. Recently, several populations of CAFs with distinct functions have been characterized in pancreatic cancer by our group and others using single cell RNA sequencing techniques. One population is characterized as myofibroblastic CAFs, another population is characterized as inflammatory CAFs, the third population was identified as antigen-presenting CAFs (apCAFs), which express MHC II molecules and can effectively present antigen to T cells. However, the origin and functions of apCAFs remain unknown. By tracing the apCAFs in a cancer progression setting, we found that they originate from a cell type called mesothelial cells in normal pancreas. Mesothelial cells form a continuous layer of epithelial cells known as mesothelium. The mesothelium is traditionally thought to be a membrane providing a non-adhesive surface covering organs and tissues. However, until the description of apCAF population, mesothelial cells have been neglected as a potential functional constituent of the tumor microenvironment. Our data suggest that during cancer progression, mesothelial cells gain fibroblast features, become a major CAF population and are involved in the direct regulation of T cells in the tumor microenvironment.

Bio/research field:

Huocong Huang is a postdoctoral researcher in the laboratory of Dr. Rolf Brekken at UT Southwestern Medical Center. His research focuses on studying stromal signaling pathways and tumor microenvironment in pancreatic cancer. He obtained his medical degree from Sun Yat-sen University, Guangzhou, China. He then joined Dr. Keith R. Johnson’s laboratory as a Ph.D. student at University of Nebraska Medical Center, Omaha, USA, which mainly focuses on understanding the functions of cadherins during tumorigenesis. During his thesis study, he made significant findings on the signaling pathway of the collagen receptor discoidin domain receptor 1 (DDR1) that leads to the up-regulation of N-cadherin in pancreatic cancer (Huang et al. J Biol Chem, 2016). Upon completion of his Ph.D., he joined Dr. Rolf A. Brekken’s laboratory at UT Southwestern Medical Center to pursue his postdoctoral training. His research in Brekken lab has focused on elucidating the functions of different components of the tumor microenvironment and exploiting their therapeutic potential for cancer therapy. His efforts have resulted in multiple important discoveries. He found that pharmacological inhibition of DDR1 significantly enhances the therapeutic efficacy of chemotherapy in multiple mouse models of pancreatic cancer (Aguilera and Huang et al. Mol Cancer Ther, 2017) and has been actively involved in the development of new generations of DDR1 inhibitors (Zhu and Huang, et al. J Med Chem, 2019). In addition, he demonstrated that TGFβ signaling blockade has therapeutic efficacy in pancreatic cancer that harbors tumor cell loss-of-function mutations in TGFBR2. He found the efficacy results from inhibition of TGFβ activity in stromal cells and provides a molecular basis for the anti-tumor effect (Huang, et al. EMBO MOL MED, 2019). This study highlights the importance of stratifying pancreatic cancer patients who might benefit from such therapy. Besides these translational studies, he is particularly interested in understanding the basic biology of stromal cells in cancer. He drove a project that exploited single cell RNA sequencing techniques to profile the cellular heterogeneity during pancreatic cancer progression in genetically engineered mouse models. This study was the first report on the dynamic changes of stromal cells during pancreatic cancer progression at single-cell resolution (Hosein, Huang, et al. JCI Insight, 2019). It also laid the ground work for his recent discovery of a novel cancer-associated fibroblast subtype that has important functions on regulating the immune microenvironment in pancreatic cancer.