Neural crest cells (NCCs) are essential embryonic progenitor cells that are
unique to vertebrates and form a remarkably complex and coordinated system of highly
motile cells. Migration of NCCs occurs along specific pathways within the embryo in
response to both environmental cues and cell-cell interactions within the neural crest
population. Here, we demonstrate a novel role for the putative Sonic hedgehog (Shh)
receptor and cell adhesion regulator, cdon, in zebrafish neural crest
migration. cdon is expressed in developing premigratory NCCs but is
downregulated once the cells become migratory. Knockdown of cdon results
in aberrant migration of trunk NCCs: crestin positive cells can emigrate
out of the neural tube but stall shortly after the initiation of migration. Live cell
imaging analysis demonstrates reduced directedness of migration, increased velocity and
mispositioned cell protrusions. In addition, transplantation analysis suggests that
cdon is required cell-autonomously for directed NCC migration in the
trunk. Interestingly, N-cadherin is mislocalized following cdon knockdown
suggesting that the role of cdon in NCCs is to regulate N-cadherin
localization. Our results reveal a novel role for cdon in zebrafish
neural crest migration, and suggest a mechanism by which Cdon is required to localize
N-cadherin to the cell membrane in migratory NCCs for directed migration.
Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy.
Significance:
Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease.
See related commentary by Garcia Garcia et al., p. 3158
Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells. Given the link between cells with stem-like properties and cancer, it is important that we identify factors that might provide a bridge between the two. Here, we identify a sub-set of chromogranin A-positive enteroendocrine cells that are positive for the developmental and cancer-associated transcription factor Brachyury in normal human small intestinal and colonic crypts. Whilst chromogranin A-positive enteroendocrine cells are also Brachyury-positive in colorectal tumours, expression of Brachyury becomes more diffuse in these samples, suggesting a more widespread function in cancer. The finding of the developmental transcription factor Brachyury in normal adult human intestinal crypts may extend the functional complexity of enteroendocrine cells and serves as a platform for assessment of the molecular processes of intestinal homeostasis that underpins our understanding of human health, cancer and aging.
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