Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far not been a viable therapeutic target. We found that the abundance of YAP mRNA, which encodes Yes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia. In genetically engineered KrasG12D and KrasG12D: Trp53R172H mouse models, pancreas-specific deletion of Yap halted the progression of early neoplastic lesions to PDAC without affecting normal pancreatic development and endocrine function. Although Yap was dispensable for acinar to ductal metaplasia (ADM), an initial step in the progression to PDAC, Yap was critically required for the proliferation of mutant Kras or Kras:Trp53 neoplastic pancreatic ductal cells in culture and for their growth and progression to invasive PDAC in mice. Yap functioned as a critical transcriptional switch downstream of the oncogenic KRAS–mitogen-activated protein kinase (MAPK) pathway, promoting the expression of genes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenic stromal response in the tumor microenvironment, and PDAC progression in Kras and Kras: Trp53 mutant pancreas tissue. Together, our findings identified Yap as a critical oncogenic KRAS effector and a promising therapeutic target for PDAC and possibly other types of KRAS-mutant cancers.

The G-protein-coupled chemokine receptor CXCR4 generates signals that lead to cell migration, cell proliferation, and other survival mechanisms that result in the metastatic spread of primary tumor cells to distal organs. Numerous studies have demonstrated that CXCR4 can form homodimers or can heterodimerize with other G-protein-coupled receptors to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor. Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells. Simultaneous, agonistdependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2 and ultimately reduced cancer cell functions such as calcium mobilization and cellular chemotaxis. Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells as well as CXCR4-mediated migration of immune cells, it is plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4. Taken together, the data illustrate a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function and perhaps tumor progression. G-protein-coupled receptors (GPCRs)2 constitute the largest family of transmembrane receptors (1, 2), and their activation by an appropriate agonist triggers signaling through G-protein ␣ (G␣) and/or ␤␥ subunits (3, 4), leading to context-dependent outcomes. GPCRs have been reported to form homodimers, homomultimers, or heterodimers with related or unrelated GPCRs (5). The resultant heterodimers often generate pharmacological outcomes that are distinct from those of GPCR homodimers. Hence, GPCR heterodimers have become attractive targets for new drug development.The G-protein-coupled chemokine receptor CXCR4 is expressed on the surface of endothelial and epithelial cells of many tissues (6, 7), and upon activation by its agonist, stromal cell-derived 1␣ (SDF1␣), CXCR4 generates signals resulting in processes that favor tissue remodeling such as hematopoiesis, angiogenesis, normal tissue maintenance and development, cell migration, and cell proliferation (8 -19). These functions make CXCR4 a key participant in cancer development, progression, and metastasis (20 -24). Clinically, expression of CXCR4 protein in tumors is used to predict tumor aggressiveness, survival probability, and metastasis-associated mortality (17,20,21,(25)(26)(27)(28). Therefore, developing agents that can inhibit the action of CXCR4 in early and advanced stages of cancer may be effective in preventing and managing metastasis (26).Cannabinoid receptors 1 (CB1) and 2 (CB2) (29, 30) are systems comprising receptors, their agonists (exocannabinoids and endocannabinoids), and enzymes for their metabolism (29,30). CB1 is highly expressed in the brain (31), whereas CB2 is expressed in a variety of other tissues (32-36). The most notable cannabinoid ...

Since its discovery, the tumor suppressor phosphatase and tensin homolog (PTEN) has become a molecule with a wide spectrum of functions, which is typically meditated through its lipid phosphatase activity; however, PTEN also functions in a phosphatase-independent manner. It is well established that PTEN regulates several signaling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), janus kinase (JAK)/signal transducers and activators of transcription (STAT), focal adhesion kinase (FAK), and more recent, extracellular signal-regulated kinase (ERK)1/2, where activation of these pathways typically leads to cancer development and progression. In regard to most of these pathways, the underlining molecular mechanism of PTEN-mediated regulation is well established, but not so much for the ERK1/2 pathway. Indeed, accumulating evidence has shown an inverse correlation between PTEN expression and ERK1/2 in several malignancies. However, the detailed mechanism by which PTEN regulates ERK1/2 is poorly understood. In this review, we discuss the role of PTEN in regulating ERK1/2 by directly targeting shc/Raf/MEK and PI3K/AKT cascades, and a putative cross-talk between the two.