Deciphering the role of hedgehog signaling in pancreatic cancer

Pancreatic cancer, mostly pancreatic ductal adenocarcinoma （PDAC）, is a leading cause of cancer-related death in the US, with a dismal median survival of 6 months. Thus, there is an urgent unmet need to identify ways to diagnose and to treat this deadly cancer. Although a number of genetic changes have been identified in pancreatic cancer, their mechanisms of action in tumor development, progression and metastasis are not completely understood. Hedgehog signaling, which plays a major role in embryonic development and stem cell regulation, is known to be activated in pancreatic cancer; however, specific inhibitors targeting the smoothened molecule failed to improve the condition of pancreatic cancer patients in clinical trials. Furthermore, results regarding the role of Hh signaling in pancreatic cancer are controversial with some reporting tumor promoting activities whereas others tumor suppressive actions. In this review, we will summarize what we know about hedgehog signaling in pancreatic cancer, and try to explain the contradicting roles of hedgehog signaling as well as the reason（s） behind the failed clinical trials. In addition to the canonical hedgehog signaling, we will also discuss several non-canonical hedgehog signaling mechanisms.

Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.

Research progress in the cell origin of basal cell carcinoma

Identification of the cell origin of human neoplasms remains a challenging but important task in cancer research.The outcomes in this area of study may allow us to design novel strategies for early cancer detection and targeted cancer therapeutics.Skin is a great organ to study cancer stem cells because stem cells in skin have been well investigated and approaches of genetic manipulation in specific cell compartments are available to mimic clinical skin cancer in a mouse model.Recently,by using different genetic engineered mouse models,several groups have tried to discover which cell type in skin was responsible for the initiation of basal cell carcinoma,the most common type of skin cancer.These studies raised more questions but also showed more ways for future investigation.

Regulation of pancreatic cancer metastasis through the Gli2-YAP1 axis via regulation of anoikis

Pancreatic cancer,mostly pancreatic ductal adenocarcinoma(PDAC),is often metastatic upon the initial diagnosis,and has a high mortality rate.However,the primary and the matched metastatic cancers often share the same driver gene mutations.1,2 Gene expression comparison between primary and metastatic PDAC tissues revealed high expression of Gli2 and YAP1 in the metastatic PDAC.Gli2 is an important player in non-canonical hedgehog signaling,and YAP1 is an essential cell polarity gene.In this study,we investigated the effects of Gli2 and YAP1 on pancreatic cancer cell function in 3D culture and in mouse models.We further determined the relationship between Gli2 and YAP1.These studies further our understanding of pancreatic cancer metastasis.

The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer

Gastric cancer is a leading cause of cancer-related mortality worldwide, and options to treat gastric cancer are limited. Fluorouracil （SFu）-based chemotherapy is frequently used as a neoadjuvant or an adjuvant agent for gastric cancer therapy. Most patients with advanced gastric cancer eventually suc- cumb to the disease despite the fact that some patients respond initially to chemotherapy. Thus, iden- tifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat gastric cancer. In this study, we discovered that residual cancer ceils following 5Fu treatment have elevated expression of hedgehog （Hg） target genes GLII and GLI2, suggestive of Hh signaling activation, Hh signaling, a pathway essential for embryonic development, is an important regulator for putative cancer stem cells/residual cancer cells. We found that high GLI1/GLI2 expression is associated with some features of putative cancer stem cells, such as increased side population. We demonstrated that GLI2 knockdown sensitized gastric cancer cells to 5Fu treatment, decreased ABCG2 expression, and reduced side population. Elevated Gtl2 expression is also associated with an increase in tumor sphere size, another marker for putative cancer stem cells. We believe that GLI2 regulates putative cancer stem cells through direct regulation ofABCG2. ABCG2 can rescue the GLI2 shRNA effects in 5Fu response, tumor sphere formation and side population changes, suggesting that ABCG2 is an important mediator for GLI2- associated 5Fu resistance. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high GLI1/GLI2/ABCG2 expression is associated with a high incidence of cancer relapse in two cohorts of gastric cancer patients who underwent chemotherapy （containing 5Fu）. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain SFu resistance. Copyright 2017, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.

Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C （XPC） are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog （Kras） or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer with these mutations. Using activated Kras, KrasTM, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasTM and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured ceils, we demonstrated that induced expression of oncogenic KR.ASG12v led to increased levels of reactive oxygen species （ROS） as well as DNA damage, and both can be suppressed by anti-oxidants. Our results suggest that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.