November 2022: Iok In Christine Chio Lab
What is the main focus of your lab?
Pancreatic ductal adenocarcinoma (PDA) is a relatively common and highly lethal malignancy. Although most PDA patients carry common pathogenic mutations (G12D, G12V) of the KRAS gene, therapeutic agents that effectively target mutant KRAS are still not available. Nonetheless, malignant activation of KRAS generates metabolic byproducts, including reactive oxygen species (ROS), that likely contribute to tumor development and drug resistance. Even though the role of ROS in cancer remains very poorly understood, one popular view posits that ROS can promote tumorigenesis, presumably through the mutagenic consequences of oxidative DNA damage. In addition to this indiscriminate activity, we recently found that ROS can also perform signaling functions in PDA cells through oxidative post-translational modification (oxPTM) of proteins at specific cysteine and methionine residues. Using ex vivo organoid models and chemical proteomic approaches, the Chio lab seeks to develop novel therapeutic approaches to pancreatic cancer by elucidating basic mechanisms of cancer redox biology.
How big is your lab currently?
My team is a group of 8
Where is your lab located?
We are located on the fifth floor of the ICRC.
What are the most exciting projects/directions in the lab at this moment?
The impact of reactive oxygen species (ROS) on cancer is complex, especially given their context-dependent ability to either promote or suppress tumorigenesis. Interpreting the effects of ROS on cellular behavior is further complicated by their dual potential to indiscriminately oxidize macromolecules or to selectively oxidize redox-reactive residues of target proteins. Indeed, the thiol group of proteinaceous cysteines can serve as a reversible redox switch that regulates distinct signaling outcomes. For example, using our pancreatic organoid model (Cell, 2015), we previously showed that redox signaling through specific cysteine residues promotes tumor cell viability in pancreatic ductal adenocarcinoma (PDA) (Cell, 2016) through protein synthesis regulation (Nature Comms, 2019). Nonetheless, it remains unclear whether redox signaling mechanisms also contribute to the high metastatic potential of PDA, and thus the dismal prognosis associated with this malignancy. In addition to cysteine, methionine residues harbor a redox-reactive sulfur atom that can be oxidized to methionine sulfoxide, and then reduced back to methionine by methionine sulfoxide reductase A (MSRA). Very recently, my group established a novel chemoproteomic approach to characterize redox changes in the methionine proteome of PDA. We found that methionine residues can act as reversible redox switches to control cancer metabolism and metastasis (Molecular Cell, 2022). Moving forward, we are developing heterobifunctional molecules to toggle methionine-based redox switches to curb metastasis. In addition, we are extending our chemoproteomic approach to characterize methionine reactivity in physiological conditions, including wound healing and tissue regeneration.
What are the model systems that your lab is using?
The Chio lab uses an ex vivo organoid system to study mouse and human pancreatic ductal adenocarcinoma (PDA). This model system, which has since been adopted in labs and hospitals worldwide, allows the culture of both normal and malignant pancreatic ductal cells at each disease stage. As a complementary approach, we use genetically engineered mouse models harboring mutant alleles of KrasG12D, p53R172H, and PdxCre as an autochthonous model of pancreatic cancer.
What are the key techniques that your lab is using?
In addition to mouse and organoid modeling, my lab utilizes chemoproteomic and metabolomic approaches to study mechanisms of redox metabolism as drivers of tumorigenesis.
What facilities or equipment does your lab absolutely rely upon? Do you use CSCI cores?
Our lab relies heavily on mass spectrometry for both metabolomic and proteomic studies. We frequently use the CSCI flow cytometry core for in vivo cell population analysis and isolation.
What would be your career advice for students/postdocs?
Innovation is not only having the courage to disrupt convention but also having the grit to transform an idea into a solution.
Are you accepting rotating students at the moment?
We are always looking for trainees who share our excitement about redox biochemistry and metabolism to join our team!
How do members of your lab celebrate accomplishments?
Research is a hard path so we celebrate every little victory, which includes completing sample collection for a big experiment! We are a foodie lab, so my lab members would often bring baked goods to the lab and we would also organize regular lab outings to try new restaurants in town.
Does your lab have any fun traditions?
Not sure if this is a (fun) tradition but at each lab member’s birthday celebration, they would share an embarrassing story or a secret talent with the lab.
What was the most exciting part about starting your new lab?
Seeing my trainees rolling up their sleeves to figure out a difficult problem and coming to my office to share ideas that excite them is by far the most gratifying experience I have had as a mentor.