Elucidate the role of ISR in the progression of pancreatic tumor and metastasis


Despite recent advances in prevention and treatment, pancreatic ductal adenocarcinoma (PDAC) remain highly aggressive and lethal due in part to their complex tumor microenvironment. Cancer-associated fibroblasts (CAFs) are a pivotal component of the TME, known for their heterogeneity and functional significance.
However, challenges persist in pinpointing CAF origins and understanding their plasticity and diverse functions, hindering therapeutic interventions. Our recent work has highlighted the role of Activation Transcription Factor 4 (ATF4), a key regulator of the Integrated Stress Response (ISR), in shaping perivascular CAFs to influence extracellular matrix organization and angiogenesis, promoting a tumor-supportive environment in PDAC (and melanoma). Given the high stromal content in pancreatic cancer, we anticipate that ISR/ATF4 may also drive tumor progression by regulating CAF function. This concept may extend to other cancers where elevated ATF4 levels have been observed. Exploring reciprocal signaling between ATF4-proficient and deficient CAFs, cancer cells, and endothelial cells will expand our understanding of ISR pathway contributions to tumor growth, aggressiveness, therapy resistance, and metastasis. Our research focuses on thoroughly examining primary tumors and metastatic niches to understand the role of ISR/ATF4, which helps in identifying potential therapeutic strategies.