The importance of the host microenvironment in regulating tumor progression has been appreciated for almost a hundred years. However, the complex interplay between different cell types in the tumor and how these interactions over time actively regulate tumor biology, drug resistance and metastasis is still poorly characterized. Recently, non-coding RNAs have emerged as critical regulators of multiple cellular processes including inter and intracellular events that establish and maintain the tumor microenvironment. My research interests are focused on understanding how non-coding RNAs shape the tumor microenvironment. Specific long-term goals of the laboratory include:
1) How microRNA-target networks shape stress responses in the tumor vasculature?
The microenvironment that supports the growth of tumors encounters a variety of insults during tumor progression. Particularly with the increasing use of genotoxic agents in cancer, there is a significant induction of DNA damage in both tumor cells and the microenvironment. While the DNA damage, cell cycle and apoptosis pathways have been elucidated in the context of tumor cells and their aberrant genomes, it is unclear how genetically normal host cells in the microenvironment perceive and respond to DNA damage. Understanding what factor(s) mediate DNA damage responses in the host cells will a) provide potential targets for sensitizing the tumor microenvironment to genotoxic stress and b) contribute fundamental mechanistic insights into how the different host cell types in the microenvironment handle insults and injuries.
I have identified specific miRs that are upregulated in endothelial cells during treatment with different stressors such as radiation, cisplatin (genotoxic stress), hydrogen peroxide (oxidative stress) and TNF-α (inflammatory stress). I have also profiled mRNAs that are downregulated in endothelial cells during genotoxic stress. Interestingly, several of these mRNAs are predicted targets for the upregulated microRNAs suggesting that a reciprocal regulation of miR-target pairs during genotoxic stress might have a powerful influence on the response of endothelial cells to these stressors.
2) Reshaping the tumor microenvironment using miR based cell engineering
Our understanding of human tumors has increased exponentially in the past decade due to the availability of high throughput ‘omics’ data. These data, in addition to confirming the heterogeneity of human cancer, also highlight the challenges in developing therapies targeted to specific molecules. An alternative approach to circumvent these challenges is to use engineered cells to both probe and attack the tumors from inside i.e. from within the microenvironment. Cell engineering approaches such as chimeric antigen receptor bearing T-cells have shown good safety and efficacy in humans thereby validating the feasibility of such approaches. My long-term goal is to utilize different miR profiles from human cells to design miR regulated constructs that can be induced by specific triggers such as radiation or hypoxia that will be restricted to the tumor microenvironment. Expression of these inducible constructs in tumor homing myeloid cells would enable the delivery of multiple cargoes that can serve as diagnostics and/or therapeutics in the tumor microenvironment.
3) The influence of non-coding RNAs on immune checkpoints
In the last few years, it has become clear that the negative regulation of immune responses plays a major role in the tumor microenvironment. Blockade of immune checkpoints such as PD-1/PD-L1 interactions, either alone or in combination with other therapies, has shown tremendous promise in the treatment of melanoma, lung cancer and kidney cancer. These strategies are now being extended for other immune co-stimulatory/co-inhibitory molecules and other types of cancers. Although it is clear that targeting these pathways work for a number of patients, there are no reliable biomarkers that can serve as prognostic indicators. Moreover, the current therapies aimed at these pathways are often antibody-based and designed to work on patients who show surface expression of these proteins. I am interested in identifying specific non-coding RNAs that can a) serve as reliable biosensors of these immune checkpoints and b) act as therapeutic targets to enhance the cell surface expression of co-stimulatory molecules or downregulate the expression of co-inhibitory molecules that will synergize with current antibody therapies.