The unfolded protein response (UPR) is an intracellular signaling network that mitigates endoplasmic reticulum (ER) stress caused by improperly folded proteins. Hostile tumor microenvironment (TME) settings and cellular oncogene activation often cause ER stress, but tumor cells utilize the UPR to circumvent it and continue their malignant growth. The key UPR sensor inositol-requiring enzyme 1 (IRE1) resides in the ER membrane and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding and thus cellular adaptation to ER stress leading to tumor progression.
In the last 8 years, we have extensively studied the biological importance of the UPR in general and IRE1 in particular in various cancers and have provided definitive preclinical evidence validating IRE1 as a potential therapeutic target for multiple myeloma and triple-negative breast cancer. Now, we are exploring the role of the UPR in different aspects of pancreatic cancer tumor growth, such as initiation, progression, metastasis, and therapy resistance.
For this, we are using a broad set of molecular biology and biochemical techniques, including transcriptome and proteome analyses, and a wide array of models, including cancer cell lines, patient-derived organoids, and primary patient samples. We are committed to translating discoveries from comprehensive basic cellular and mechanistic studies into novel, innovative therapies for cancer.