What Cells Prevent Pancreatic Cancer Progression?

What Cells Prevent Pancreatic Cancer Progression?

Tuft cells inhibit progression of inflammation-induced pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDA), researchers report in the November issue of Gastroenterology. These unique cells were found to suppress tumor progression via secretion of lipid eicosanoid mediators.

During PDA progression, the number of DCLK1+ tuft cells gradually decrease and are associated with an anti-tumor phenotype, indicating the heterogeneity and plasticity of these cells.

Tuft cells are solitary chemosensory cells found throughout organs of the respiratory and digestive tracts. They can be identified by their long, blunt microvilli, deep actin rootlets, and extensive tubulovesicular system in the supranuclear cytoplasm. Tuft cells coordinate with the immune and nervous systems to protect the body from pathogen invasion, injury, and harsh microenvironment. Lineage-tracing studies identified tuft cells as cells of origin for inflammation and inflammation-associated KRAS-driven tumors.

PDA development involves acinar to ductal metaplasia and genesis of tuft cells. Although these cells increase during the genesis of PanIN, they are not detected in PDAs (see figure). Kathleen E. DelGiorno et al investigated the role of tuft cells in pancreatic tumorigenesis by disrupting a gene required for tuft cell development, Pou2f3, in mice that express an activated form of KRAS (KC mice).

Surprisingly, the authors found that tuft cell ablation accelerated tumorigenesis, indicating a protective role for tuft cells during pancreatic tumor progression.

Pancreata from KC mice had increased formation of tuft cells (based on markers such as DCLK1) and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice resulted in loss of tuft cells and accelerated tumorigenesis. These KPouC mice had increased increased pancreatic injury, fibrosis, and activation of immune cells after administration of caerulein, which promotes inflammation and pancreatitis. Pancreata from KPouC mice also had significantly lower levels of prostaglandin D2 than KC mice, significantly less normal tissue, more extracellular matrix deposition, and a higher PanIN grade than KC mice.

Transcriptome analysis of KC tuft cells identified alterations in lipid synthesis and metabolism pathways. The cells had significant enrichment of eicosanoid synthases, including lipoxin, leukotriene, and PG synthases. Tuft cell-derived prostaglandin D2 (PGD2) suppressed pancreatic tumorigenesis in KC mice.

To ascertain any structure–function relationships in pancreatic tuft cells, DelGiorno et al conducted detailed ultrastructural analyses of pancreata from 1-year-old KC mice using scanning electron microscopy and serial blockface electron microscopy. These analysis captured the topography of PanIN, including the long, blunt microvilli characteristic of tuft cells. The authors found that lipid droplets serve as sites of eicosanoid synthesis in KC tuft cells.

The authors performed laser-capture dissection and RNA-sequencing analysis of pancreatic tissues from 26 patients with PanINs, 19 patients with intraductal papillary mucinous neoplasms (IPMNs), and 197 patients with PDA. Human PanINs and intraductal papillary mucinous neoplasms had gene expression signatures associated with tuft cells and increased levels of Hpgds mRNA, which encodes a protein involved in eicosanoid metabolism, compared with PDA. Disruption of Hpgds in the epithelia resulted in greater pancreatic injury and significantly less normal tissue. HPGD metabolizes PGD2 into 13,14-dihydro-15-keto PGD2, which is thought to have greater tumor-suppressive effects than PGD2 itself.

In a model, DelGiorno et al propose that that in KC mice, tuft cells use local paracrine PGD2 signaling to curb activation of the tumor microenvironment and reduce pancreatic cancer progression. These findings indicate the importance of eicosanoid signaling in PDA development.

In an editorial that accompanied the article, Landon L. Moore et al wrote that these findings demonstrate a role for tuft cells in tumor inhibition, via alterations in gene expression and signaling pathways. Further studies are need of the balance of tumor-promoting and -suppressing signals in these cells.