Elucidate the role of the tumor-stroma crosstalk in tumor progression and drug resistance
The TME is a complex combination of several different cell types (tumor cells, fibroblasts, endothelial cells, and immune cells) and molecules (ECM, cytokines, chemokines, enzymes and growth factors) and is a key contributor to malignant progression. Over the last years, a robust body of evidence has highlighted the importance of the crosstalk between tumor and stroma. Cellular and non-cellular components have been associated with different clinical outcomes, as well as with response in cancer patients. Classic tissue culture models fail to account for the complexities of human tumors, mainly due to the absence of recreation of the TME in which the tumor exists, including surrounding accessory cells, signaling molecules, oxygen content, and the ECM. Cell behaviors within tissues are predicated upon 3D interactions with ECM and other cells, and it is clear that traditional 2D cultures are insufficient to mimic real tissue architecture. Engineered TME will be made in our laboratory made of patient’s plasma preserving non-cellular and cellular components from the same patient. We hypothesized that the behavior of cancer cells in the engineered TME will closely mimic the behavior of cancer cells in the patients; and therefore this model will provide better prediction of tumor progression and drug resistance.
Investigate the role of TME physical features on cancer immune escape
The tumor microenvironment is a complex heterogeneous assembly composed of a variety of cell types and physical features. One such feature, hypoxia, is associated with several biological processes critical for cancer progression, epithelial-mesenchymal transition (EMT), migration/invasion, maintenance of cancer stem cells (CSCs) and the associated CSC niche, metastasis, immune surveillance and resistance to chemotherapy. It is generally accepted that the oxygen level in hypoxic tumor tissues is poorer than the oxygenation of the respective normal tissues and on average it is between 1–2% O2 and below. There is evidence that oxygen influences many immune cells, including T cells, tumor-associated macrophages, neutrophils, NK cells, and B cells. It is thus reasonable to speculate that realistic in vitro models should also be able to recreate hypoxia. We hypothesize that the tumor hypoxia induces structural and cellular changes in the TME that reduces the efficacy of the immune cells to target cancer cells and that targeting hypoxia will sensitize cells to interactions with immune cells.
Translational Research: Personalized medicine
Our lab is developing personalized 3D models of the tumor microenvironment of cancer patients to retrospectively and prospectively evaluate therapeutic efficacy to cancer treatment. These models have the potential to be utilized for high throughput drug testing for prediction of drug sensitivity and can be used in personalized medicine to study novel therapeutic targets for individual cancer patients. The final goal is to enable clinicians to build personalized treatment strategies for individual patients based on the ex vivo drug sensitivity of cancer cells.