We investigate how specific alterations in gene regulation, including changes in signaling and transcription, impact the pathogenesis and therapeutic response of cancer. Our research aims to understand the plastic nature of cancer cells and their gene regulatory networks, which affect tumor progression and therapy response. One of the primary objectives of our studies is to identify and target the key regulators of cancer cell adaptation, to reverse or prevent therapy resistance. To achieve this, we utilize functional genomics, including the genome editing tool Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), assessing the functional significance of regulators among epigenetic, transcriptional, and signaling genes. Using CRISPR in combination with High-throughput sequencing-based methods, we can efficiently screen large sets of potential target genes in vitro and in vivo. By combining CRISPR screening with single-cell, spatial genomics, and DNA barcoding, we can track cancer cell adaptations during therapy and pinpoint the key transcriptional regulators of cell state transitions, thereby gaining a deeper understanding of adaptive resistance. These methods will help us to identify new therapeutic targets to prevent or reverse therapy resistance.

Investigating the transcriptional regulatory networks and identifying vulnerabilities of cell state transitions in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human cancers. A significant contributing factor to this disease’s aggressiveness is cancer cell plasticity, which leads to accelerated disease progression, metastatic spread, and therapy resistance. Tumor cell plasticity results in the coexistence of cells in different states, like classical, basal, and mesenchymal, with the ability to switch between these transcriptional phenotypes. Observing these changes has been only the first step in understanding why and how cells enter different cell states to escape therapy and metastasize. What remains unclear is which stimuli lead to changes in phenotypic cell states in vivo and which gene regulatory networks play the key role. Our group will utilize functional genomics in vivo to identify these networks and pinpoint the key regulators that allow cells to transition between different cell states. Targeting these regulators will enable us to manipulate and reprogram cancer cells in a manner that resensitizes tumor cells to therapy or prevents the development of resistance.