4 research outputs found
Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells
Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers
Summary: Mutant KRAS and c-MYC are oncogenic drivers and rational therapeutic targets for the treatment of pancreatic cancer. Although tumor growth and homeostasis are largely dependent on these oncogenes, a few residual cancer cells are able to survive the ablation of mutant KRAS and c-MYC. By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, we have identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. The pharmacological inhibition of IGF-1R reduces residual disease burden and cancer recurrence, suggesting that this molecular pathway is crucial for the survival of cancer cells in the absence of the primary oncogenic drivers. : Rajbhandari et al. demonstrate that an increase in autocrine IGF1 signaling mediates the survival of residual pancreatic cancer cells following the ablation of oncogenic drivers (mutant KRAS and c-MYC). They provide experimental evidence that inhibiting IGF-1R can eradicate minimal residual disease and reduce cancer recurrence in vivo. Keywords: pancreatic cancer, oncogenes, KRAS, c-MYC, cancer dormancy, mouse models, genetic engineering, IGF1 signaling, AK
Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression
Summary: Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kinase 1, we show here that JAK1 is essential for IL-6-class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling, which promotes tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6-class cytokines, which are master regulators of cancer-associated inflammation. : Wehde et al. demonstrate that JAK1 is the pivotal kinase that controls cytokine-mediated activation of three STAT proteins in ERBB2-driven mammary cancer cells. They provide experimental evidence that deficiency in JAK1/STAT3 signaling and consequential downregulation of oncogenic targets inhibit migration, tumorsphere formation, and metastatic dissemination of mammary cancer cells. Keywords: breast cancer, mammary neoplasms, Janus kinase 1, Stat transcription factor, gene targeting, signal transduction, Cre recombinase, RNA sequencing, c-Fos, MAP3K
Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells
The cellular origin and oncogenic drivers promoting claudin-low breast cancer are undefined. Here, the authors report that the consistent activation of oncogenic RAS signaling, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells