Laboratory of Tumor Microenvironment and Therapeutic Resistance
The long-term goal of our lab is to conduct a comprehensive investigation that defines the dialogues of heterogeneous tumor cell subtypes, and the vasculature and immune cells in the distinct tumor vascular niches in response to standard as well as targeted therapies including antiangiogenic and immune-modulating therapies. The results forthcoming, will enable us to identify suitable polytherapies that are adapted to the heterogeneous cancer responses to more successfully impede therapeutic resistance and prolong survival.
Cancers are heterogeneous entities in which tumor cell populations as well as distinct host cell constituents form a dynamic and interactive tumor community that is pivotal not only for the genesis and progression of a tumor but also for the tumor’s ability to resist therapeutic elimination. Extensive characterization of the genome, epigenome and transcriptome of tumor cells has provided a higher-resolution picture of their alterations revealing substantial inter- and intra-tumor heterogeneity. A further layer of complexity arises from the different normal host cell constituents within the tumor that comprise the tumor microenvironment. They are composed of a wide variety of non-neoplastic stromal cells, of which the vasculature with its endothelial cells and pericytes, and the various infiltrating and resident immune cells are dominant inhabitants in all tumors while the type and abundance of other cell types can be more tissue-specific.
Importantly, tumor cells and host cell constituents can form microanatomical compartments within the tumor to regulate metabolic needs, immune surveillance, survival, invasion, metastasis and cancer stem cell (CSC) maintenance. These microenvironmental niches exhibit communication centers in which tumor and host cell populations dynamically interact via direct cell contact or paracrine signaling cues to ensure maintenance, growth and protection of tumor cells and CSC from immune surveillance and therapeutic threats. Although tumor niches have been portrayed as conceptually similar in a variety of tumor types, there exist distinct specialized tumor niches of which the vasculature is an integral regulatory part. Taking advantage of various transgenic and orthotopic mouse models of tumorigenesis and human tumor tissue samples, we have predominantly been studying vascular niches in glioblastoma (GBM), pancreatic neuroendocrine tumors (PNET) and breast cancer. Thereby, our lab has identified several mechanisms of resistance to antiangiogenic therapy that are either driven by tumor cells or immune cells.
- Understanding mechanistic underpinnings of tumor-microenvironment-governed resistance with a focus on tumor cell heterogeneity.
- Tumor vascular modulation to enhance therapeutic efficacy.
- Explore new avenues to create enduring immune-stimulating effects in primary tumors and metastatic lesions.
Our work is supported by: