Overview
Research Project Leader: Aaron Hobbs, Ph.D.
Dr. Hobbs’s research focused on defining how distinct oncogenic KRAS mutations drive pancreatic cancer through unique signaling programs and protein interaction networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a very high prevalence of KRAS mutations, which are critical drivers of tumor initiation and progression. This project tested the hypothesis that different KRAS mutations engage distinct effector pathways and therefore create mutation-specific therapeutic vulnerabilities that can be selectively targeted. By moving beyond the traditional view of KRAS as a single undruggable oncogene, this work established a framework for precision targeting of KRAS-driven cancers based on mutation-specific biology.
Specific Aims
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Determine KRAS mutation-specific protein interaction networks and signaling pathways using proximity labeling approaches
- Define mutation-specific therapeutic vulnerabilities of KRAS signaling in both 2D and 3D pancreatic models, including organoids
Research Approach
The project combined proteomics, molecular biology, and advanced model systems to interrogate KRAS signaling. Proximity-dependent biotinylation (TurboID/BioID) was used to map mutation-specific KRAS interactomes in isogenic pancreatic cell systems, enabling identification of both stable and transient signaling partners. These studies were extended from traditional 2D cultures into 3D organoid systems derived from mouse pancreas to better recapitulate tissue architecture and signaling context. Functional validation of key pathways was performed using genetic and pharmacologic perturbations to define signaling dependencies required for tumor initiation and proliferation.
Use of the Center's Core Resources
Cell Models Core
- Development of pancreatic organoids and engineered cell systems for mutation-specific KRAS studies
Proteomics Resources
- Mass spectrometry analysis of TurboID-derived KRAS interactomes
Animal Models Core
- Generation and analysis of KRAS-driven mouse models and organoid systems
Innovation
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Establishes that KRAS mutations are functionally distinct rather than equivalent drivers of pancreatic cancer
- Applies proximity labeling (TurboID) to define mutation-specific signaling networks in living cells
- Integrates 2D and 3D organoid models to capture physiologically relevant signaling dependencies
Impact and Outcomes
This work provides a mechanistic foundation for precision oncology approaches in pancreatic cancer by identifying mutation-specific KRAS signaling pathways that can be therapeutically targeted. The development of organoid-based models and proteomic workflows expands the capabilities of the CDLD research infrastructure and supports future translational studies. Participation in the
Center for Biomedical Research Excellence in Digestive & Liver Disease facilitated Dr. Hobbs' transition to independence and established a research program focused on oncogenic signaling, cancer biology, and targeted therapeutic development.
