Publications by authors named "Alicia K Fleming Martinez"
Protein kinase D1 - A targetable mediator of pancreatic cancer development.
Biochim Biophys Acta Mol Cell Res
February 2024
Members of the Protein kinase D (PKD) kinase family each play important cell-specific roles in the regulation of normal pancreas functions. In pancreatic diseases PKD1 is the most widely characterized isoform with roles in pancreatitis and in induction of pancreatic cancer and its progression. PKD1 expression and activation increases in pancreatic acinar cells through macrophage secreted factors, Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling, and reactive oxygen species (ROS), driving the formation of precancerous lesions.
View Article and Find Full Text PDFThe innate immune system has a key role in pancreatic cancer initiation, but the specific contribution of different macrophage populations is still ill-defined. While inflammatory (M1) macrophages have been shown to drive acinar-to-ductal metaplasia (ADM), a cancer initiating event, alternatively activated (M2) macrophages have been attributed to lesion growth and fibrosis. Here, we determined cytokines and chemokines secreted by both macrophage subtypes.
View Article and Find Full Text PDFArticle Synopsis
- Desmoplasia surrounding pancreatic lesions creates a barrier that hinders immune cell infiltration, and it's a key characteristic of pancreatic cancer development.
- The study reveals that alternatively activated macrophages (AAM) interact with both pancreatic lesion cells and pancreatic stellate cells (PSCs) to promote fibrosis and tumor progression, largely through the secretion of TGFβ1.
- TGFβ1 not only activates PSCs, increasing TIMP1 expression crucial for fibrosis, but also drives changes in cadherin expression that facilitate the growth and structural collapse of pancreatic lesions, highlighting its role in cancer progression.
Article Synopsis
- * Researchers found that while PanIN cells have mutated KRas and increased EGFR activity, EGFR signaling does not reach the nucleus in DCLK1 PanIN cells, indicating a unique signaling pathway.
- * Inhibition of EGFR with drugs like erlotinib unexpectedly leads to an increase in DCLK1 PanIN cells by raising hydrogen peroxide levels, which activates PKD1, promoting stemness in these cancer cells and highlighting a potential therapeutic target.
The differentiation of acinar cells to ductal cells during pancreatitis and in the early development of pancreatic cancer is a key process that requires further study. To understand the mechanisms regulating acinar-to-ductal metaplasia (ADM), ex vivo 3D culture and differentiation of primary acinar cells to ductal cells offers many advantages over other systems. With the technique herein, modulation of protein expression is simple and quick, requiring only one day to isolate, stimulate or virally infect, and begin culturing primary acinar cells to investigate the ADM process.
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