Defining the determinants of the response to therapeutic exposure in cancer

Cancer cells incorporate a large number of internal and external cues as they execute oncogenic processes. The treatment of cancer induces complex molecular changes across these programs. These are dependent on the mechanism of action of the applied therapy as well as due to differences in genetic background both between patients and within an individual tumor. Defining the regulation of these innate and treatment-induced landscapes can identify successful points of therapeutic intervention. The Chemical Genomics Laboratory at Columbia aims to leverage cutting-edge multiplex single-cell genetic and chemical genomics tools to generate these maps of cellular response.

Our approach

Multiplex single-cell chemical transcriptomics

Image depicts theoretical responses of two different cell types to therapeutic exposure. In the top example, treatment induces multiple discrete cellular states. In the bottom example, exposure results in a continuum of responses. Both of these responses can only be adequately described using techniques at single-cell resolution.

Our sci-Plex multiplexing strategy enables the coupling of high-throughput chemical screens to single-cell RNA-seq. We aim to use this platform to characterize the molecular effects of the treatment of tumor cells to thousands of unique therapeutic exposures. Our goal is to leverage these atlases to uncover cell type and cell state specific responses that present vulnerabilities or paths to resistance that can inform new therapeutic strategies. 

CRISPR-based single-cell molecular screens

Image depicts an example of an experiment to define the contribution of individual genes to a therapy induced response. Top depicts a signaling pathway targeted by a drug. Colors depict individual components and viruses of the same color encode CRSIPR guide RNAs targeting that pathway component. Bottom depicts transduction of Cas9 expressing cells with guide RNAs against pathway components.

Single-cell pooled CRISPR screens allow for the molecular characterization of the effect of many genetic perturbations in parallel. Combined with chemical transcriptomics these screens enable the dissection of the contribution of individual genes to drug-induced molecular responses. We aim to use these techniques to identify the gene regulatory networks causative for individual aspects of the complex response initiated by tumor cells after therapeutic exposure. 

In vivo single-cell perturbation genomics

Cartoon depicts the effects of genetic heterogeneity and drug exposure on tumor composition and associated molecular signatures.

We are interested in developing and extending our tools for single-cell perturbation screens to determine how genetic and chemical perturbations interact to drive therapeutic response in tissues. Combined with our large-scale in vitro efforts, these approaches will allow us to identify the molecular changes associated with response to therapy in the context of the complex interactions between cancer cells and their environment.