ADAM10 regulates Notch function in intestinal stem cells of mice.

Background & Aims: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a cell surface sheddase that regulates physiologic processes, including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types, but the requirement for ADAM10 signaling in crypt homeostasis is not well defined.

Methods: We analyzed intestinal tissues from mice with constitutive (Vil-Cre;Adam10(f/f) mice) and conditional (Vil-CreER;Adam10(f/f) and Leucine-rich repeat-containing GPCR5 [Lgr5]-CreER;Adam10(f/f) mice) deletion of ADAM10.

Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.

We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC.

Towards patient-based cancer therapeutics.

A new approach to the discovery of cancer therapeutics is emerging that begins with the cancer patient. Genomic analysis of primary tumors is providing an unprecedented molecular characterization of the disease. The next step requires relating the genetic features of cancers to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

Metalloproteinases and cell fate: Notch just ADAMs anymore.

Notch signaling is involved both in development as well as in multiple cancers, including pancreatic cancer. Its activity has been implicated early in pancreatic disease, shown to be essential for a pre-cancerous transdifferentiation event known as acinar-to-ductal metaplasia (ADM). Recently, we have shown that matrix metalloproteinase-7 (MMP-7) is essential for ADM by activating the Notch pathway, challenging the notion that ADAM metalloproteinases are the sole enzymes responsible for initiating Notch activity.

Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway.

Acinar-to-ductal metaplasia in the pancreas is associated with an increased risk for tumorigenesis. Molecular dissection of this process in vitro has shown that primary acinar cells, in response to EGF receptor ligands, can transdifferentiate into duct-like epithelia, passing through a nestin-positive intermediate, in a Notch pathway-dependent manner. Here, we show that in vitro acinar transdifferentiation depends on matrix metalloproteinase 7 (MMP-7), a proteinase expressed in most metaplastic epithelia in vivo.