Neutrophils are the first responder cells to sites of infection and tissue damage. Evidence from patient tumors and animal models of cancer also suggest that they are highly recruited to the tumor microenvironment, though their role there is still poorly understood. The larval zebrafish is an excellent model to study neutrophil migration and chemotaxis in vivo and is an emerging model for cancer development and progression. Here, we use the zebrafish to model Kras-driven oncogenesis in keratinocytes and glial cells. Beginning at 3 days post fertilization (dpf), we observe invasive EMT-like cell shape changes in oncogenic mutant Kras (KrasG12V) expressing cells as well as enhanced cell proliferation as marked by phospho-histone H3. Using fluorescently labeled transgenic lines, we demonstrate that neutrophils are recruited to transformed cells and that blocking this recruitment results in decreased proliferation of transformed cells, suggesting that neutrophils may play a tumor-promotional role in our model. To determine the method of neutrophil chemotaxis to transformed cells, we used Transcription Activator-like Effector Nuclease (TALEN) mutagenesis to generate zebrafish mutants for the chemokine receptor CXCR1, which is known regulate neutrophil chemotaxis. We demonstrate that CXCR1 is required for neutrophil chemotaxis to a tail-transection wound and to Kras-transformed cells in zebrafish. Together these data suggest that blocking CXCR1 activity may reduce neutrophilic inflammation in the tumor microenvironment which may in turn reduce tumor cell proliferation and slow tumor progression.
Citation Format: Davalyn Powell, Qing Deng, Anna Huttenlocher. CXCR1 is required for neutrophil recruitment to wounds and Kras-transformed cells in zebrafish [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A117.
- ©2016 American Association for Cancer Research.