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 which can form microanatomical niches within the tumor to regulate metabolic needs, immune surveillance, survival, invasion, metastasis and cancer stem cell (CSC) maintenance and protect them from therapeutic threats. 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. Consequently, neovascularization and immune suppression have become important hallmarks of cancer.

Indeed, tumors are determined to use various strategies involving innate and adaptive immune cells to override angiogenesis inhibition and convey immune suppression. With the observation that an immunostimulatory environment promotes antiangiogenic activity, and antiangiogenic drugs promote an immunostimulating environment, we discovered the formation of high endothelial venules in tumors that foster lymphocyte trafficking, and subsequently improved outcome.

Various angiogenesis inhibitors targeting the VEGF/VEGFR pathway were developed and some FDA/EMA-approved for a variety of cancers. Despite beneficial effects in some patients, antiangiogenic therapy has unfortunately not fulfilled expectations because it aids only a subset of cancer patients and provides only transitory improvements.Using various mouse tumor models, we discovered over the years several adaptation mechanisms of tumors to antiangiogenic therapy including a switch from angiogenic to a non-angiogenic growth by coopting existing blood vessels, upregulation of alternative proangiogenic factors in tumors and implication of immune cells.

The overarching goal of our team is to conduct a comprehensive investigation that defines the dialogues of heterogeneous tumors with the vasculature and immune cells in the distinct tumor vascular niches in space and time during progression and targeted therapies including antiangiogenic and immune-modulating therapies. We will continue to take advantage of various transgenic and orthotopic mouse models of tumorigenesis an dintratumor heterogeneity  (GBM, pancreas, breast) and human tumor tissue samples, using state-of-the-art technologies at the VIB including single cell RNAseq, spatial transcriptomics and metabolomics. We seek therapeutic strategies to rigorously investigate how the microenvironment contributes to tumor progression and therapy-induced adaptation and resistance, and consequently tackle these obstacles therapeutically.

Current topics:

• Investigate the intimate regulation of the vascular and immune system in cancer
• Modulate  the tumor vasculature into high-endothelial venules to enhance immune response and boost immunotherapy.
• Explore new avenues to create enduring immune-stimulating effects in primary tumors and metastatic lesions.
• Understand mechanistic underpinnings of tumor-microenvironment-governed resistance with a focus on tumor cell heterogeneity.