Hwang et al. Page 1147

The importance of the Hedgehog (Hh) pathway has been shown recently in several malignancies and in pancreatic cancer models. Signaling is thought to involve paracrine interactions with the tumor microenvironment. Hwang and colleagues found that the Smoothened (SMO) receptor is highly expressed in pancreatic stellate cells (PSC) but not in pancreatic cancer cells, whereas the converse pattern was seen for Hh ligands. Stimulation of the Hh pathway increased PSC activity, which was reversed by a novel SMO inhibitor (AZD8542). Using a coinjection mouse model with PSCs, the authors show that not only did PSCs increase pancreatic tumor growth but also that inhibition by AZD8542 was highly dependent on the presence of PSCs expressing SMO. Furthermore, AZD8542 treatment increased tumor vascularity. These results emphasize the crucial contribution of PSCs in the tumor microenvironment and can help guide future clinical trials involving Hh inhibitors for pancreatic cancer.

Switzer et al. Page 1203

Based on an earlier observation that increased inducible nitric oxide (NO) synthase in estrogen receptor–negative breast cancer is associated with epidermal growth factor receptor (EGFR) phosphorylation and a stem cell–like phenotype, Switzer and colleagues examined the mechanism of NO-induced EGFR activation. They discovered that NO activates EGFR and Src by a mechanism that includes S-nitrosylation, leading to oncogenic c-Myc, PI3K/Akt, STAT3, and β-catenin signaling; loss of PP2A tumor suppressor activity; and a stem cell–like phenotype. NO signaling also increased chemoresistance to doxorubicin and paclitaxel. Thus, NO signaling may induce therapy resistance, and its inhibition may lead to improved outcomes in breast cancer.

Muñoz et al. Page 1216

Munoz and colleagues describe a novel mechanism of growth promotion in cancer cells in which the mitogen hepatocyte growth factor (HGF) can enhance alternative splicing of the tumor suppressor gene, Kruppel-like factor 6 (KLF6), into a growth-promoting splice isoform, SV1. Although it is known that SV1 can promote metastasis in human cancer, the extracellular signals that drive its generation remain obscure. In cultured cells, HGF promotes Akt phosphorylation, which in turn downregulates 2 splice regulators, SRSF3 and SRSF1, to enhance KLF6 splicing. These findings link a well-known mitogen to abrogation of a tumor suppressor pathway, uncovering new potential targets for growth-suppressive therapies in tumors in which KLF6 splicing activity is high.

Appleman et al. Page 1228

There is a need for a clearer understanding of the consequences of KRAS activation in pancreatic ductal adenocarcinoma (PDAC) initiation and progression. In this study, Appleman and colleagues determined the signaling pathways activated by KRASG12D and BRAFV600E in primary pancreatic ductal epithelial cells (PDEC) and found that KRASG12D- and BRAFV600E - expressing PDECs depend on a novel MEK/IGF1R/PI3K signaling axis for cell survival after apoptotic challenge and tumor formation in an orthotopic model. Furthermore, they show that combined inhibition of MEK and IGF1R impairs pancreatic cancer cell survival. These findings identify key signaling mechanisms and suggest novel therapeutic strategies that might be applied to PDAC.