Mapping immune cell heterogeneity in the tumor and beyond
Blood vessels are the gateways to the tumor for cells and drugs. Distinct neighborhoods of cells develop along these routes. The 3D structure of the vascular network is intimately tied to it’s function, which mean we need to take our imaging to the 3rd dimension. How does the vascular network influence local cell states and vice versa? We use spatial transcriptomics, imaging and in vivo genetic perturbation tools to tease apart this network.
How do extracellular proteases remodel the tumor microenvironment? And how do they affect responsiveness to immunotherapy. We seek to develop tools to image their activity in situ and correlate to gene expression in the local neighborhood.
Fibroblasts can exert significant effects on the immune compartment of the tumor including ECM deposition, production of cytokines and direct antigen presentation. How are their gene expression patterns correlated with nearby immune cells and how does this change with immunotherapy?
The lymph node serves as a major organizing center for immune responses where antigens, signaling molecules, and cells come together in a tightly organized fashion. How do these remarkable structures determine the course of the anti-tumor response and how can we generate similar structures peripheral to the tumor including tertiary lymphoid structures?
Developing and refining new computational tools and technology
Gene programs represent potentially conserved basic elements of tissue biology. We are broadly interested in computational tools to extract them, correlate them across tissue contexts and use them to inform the upstream gene regulatory networks that drive them.
The field of spatial transcriptomics is rapidly growing, seeking to link the 3 dimensions of space with the many thousands of genes in transcriptomics space. We seek to utilize newly developed approaches such as ZipSeq to tackle questions around spatial tissue heterogeneity and how it arises and influences local immune cell activity.
We also seek to build on these approaches, adding new modalities, increasing their throughput with automation, increasing their resolution, as well as creating entirely new techniques integrating new photochemistry and genetic tools.