Research

Developmental Signaling Pathways Controls Cell Migration

The image shows a flock of birds, representing a uniform layer of epithelial cells, sitting on an electric wire. The power transformer (yellow) represents the Frizzled 2 receptor, which promotes migratory behavior. 

Developmental Signaling Pathways. We study the developmental signaling networks that let cells change from quiescent to proinflammatory, migratory, and proliferative. This process is relevant in organ fibrosis, and in cancer. The external signal that we study is called Wnt, which is a protein released by cells that stimulates nearby cells or the cells that produce it by binding to a receptor protein on the membrane called Frizzled 2 (Fzd2). The Wnt-Fzd2 pathway activates protein kinases that ultimately change the activity of transcription factors to alter the expression of genes associated with reduced cell adhesion, increased degradation of the extracellular matrix, enhanced cell migration, and production of inflammatory signaling proteins called cytokines. Activation of this pathway stimulates a change in cell state that contributes to pathological conditions; thus, this pathway represents a target for therapeutic intervention.

Our lab’s goal is to provide molecular details and tools for studying this pathway and other clinically important developmental signaling pathways with the ultimate goal of enabling pharmacological manipulation to treat disease.    Read More


Signaling Networks Withing Tissue Microenvironment

Signaling Networks Within Tissue Microenvironment. Traditionally, signaling networks have been studied and dissected in the context of single-cell and single-cell populations. On the other hand, it is also well-established that the cellular microenvironment, which is highly dynamic and heterogeneous, exerts critical influences on signaling networks. However, the community has lacked experimental approaches to study cell-cell interactions and single-cell responses in complex tissues. To address these challenges, the Gujral lab is developing new strategies that will enable studies of signaling networks in the tissue microenvironment.

Organotypic tissue slices as a state-of-the-art-model for mechanistic and drug discovery studies. We have been developing methods for maintaining thin sections of mouse and patient-derived tumor slices for mechanistic and drug discovery studies. These preparations are called organotypic tissue slices, and they preserve the organization and heterogeneity of the cells and extracellular structures within the tumor tissue. The tumor tissue slices are 200 – 250 μm thick, representing ~10 layers of cells, and include cancer cells, normal cells, and immune cells in this tumor microenvironment. We have optimized the conditions to maintain the viability of organotypic tumor tissue slices for several weeks in culture. We have also developed methods for the delivery of small molecules using an active flow-based perfusion system. We demonstrated the utility of this ex vivo model system for medium-throughput cytotoxic and immuno-oncology drug screening studies (published in OncoImmunology, 2019, JoVE, 2020, and Lab Chip, 2021, Gut, 2022). In collaboration with Dr. Albert Folch (University of Washington, Bioengineering, our lab is developing approaches to integrate organotypic slices with microfluidics to study tumor-host cell interactions within the organized tumor microenvironment.  Read More

 


Metastases are responsible for as much as 90% of cancer-associated deaths. This is because we continue to struggle with how to develop drugs for metastatic cancers. Metastatic cancers occur when cancer cells spread from their organ of origin (called the primary cancer site) to another organ (called the secondary or metastatic site). Metastasis is exceptionally dangerous as it usually affects essential organs such as the brain, lungs, and liver. The destruction of these organs by metastases results in rapid decline and failure. Unfortunately, drugs that are effective in treating localized cancer, that is, cancer that’s contained within the primary cancer site, usually show little efficacy in thwarting the same cancer at the secondary site. That’s because the behavior of cancer cells and their response to therapy are influenced by the specific environment that surrounds them, the tumor microenvironment (TME). The TME varies significantly between the primary and secondary sites. As a consequence, the 5-year relative survival rate for metastatic breast cancer is only 28%. Our goal is to change the statistics by inventing a new way to discover drugs for metastatic cancers. 

Our vision for changing the status quo is based on the research philosophy that embraces complexity. Experimentally, we use new, organotypic models that preserve the native TME and apply state-of-the-art drug screening to understand drug responses on the level of both signaling pathways and individual targets. Finally, we leverage artificial intelligence (AI)-based algorithms to predict responses to thousands of candidate therapies. 

Targeting Metastases

Embracing complexity to identify organ site-specific therapies and therapeutic targets