Search

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the result of a disproportionate deposition of extracellular matrix (ECM) proteins. Cancer-associated fibroblasts (CAFs) are the main mediators of PDAC desmoplasia. CAFs represent a heterogenous group of activated fibroblasts with different origins and activation mechanisms. microRNAs (miRNAs) are small non-coding RNAs with critical activity during tumour development and resistance to chemotherapy. Increasing evidence has revealed that miRNAs play a relevant role in the differentiation of normal fibroblasts into CAFs in PDAC. In this review, we discuss recent findings on the role of miRNAs in the activation of CAFs during the progression of PDAC and its response to therapy, as well as the potential role that PDAC-derived exosomal miRNAs may play in the activation of hepatic stellate cells (HSCs) and formation of liver metastasis. Since targeting of CAF activation may be a viable strategy for PDAC therapy, and miRNAs have emerged as potential therapeutic targets, understanding the biology underpinning miRNA-mediated tumour cell-CAF interactions is an important component in guiding rational approaches to treating this deadly disease. [ABSTRACT FROM AUTHOR]

BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ~80% of BRAFV600-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of BrafV618E (analogous to the human BRAFV600 mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of BrafV618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes. A fundamental goal of current studies is to identify those somatic events arising in the variable landscape of PDA genomes that can be exploited for improved clinical outcomes. Methods: We used DNA content flow sorting to identify and purify tumor nuclei of PDA samples from 50 patients. The genome of each sorted sample was profiled by oligonucleotide comparative genomic hybridization and targeted resequencing of STAG2. Transposon insertions within STAG2 in a KRASG12D driven genetically engineered mouse model of PDA were screened by RT-PCR. We then used a tissue microarray to survey STAG2 protein expression levels in 344 human PDA tumor samples and adjacent tissues. Univariate Kaplan Meier analysis and multivariate Cox Regression analysis was used to assess the association of STAG2 expression relative to overall survival and responses to adjuvant therapy. Finally RNAi based assays with PDA cell lines were used to assess the potential therapeutic consequence of STAG2 expression in responses to 18 therapeutic agents. Results: STAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon mediated disruption of STAG2 in a KRASG12D genetically engineered mouse model promotes the development of PDA and its progression to metastatic disease. There was a statistically significant loss of STAG2 protein expression in human tumor tissue (Wilcoxon- Rank test) with complete absence of STAG2 staining observed in 15 (4.3%) patients. In univariate Kaplan Meier analysis nearly complete STAG2 positive staining (> 95% of nuclei positive) was associated with a median survival benefit of 6.41 months (p = 0.031). The survival benefit of adjuvant chemotherapy was only seen in patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; p = 0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in pancreatic cancer patients. Finally, we show that RNAi mediated knockdown of STAG2 selectively sensitizes human PDA cell lines to platinum-based therapy. Conclusions: Based on these iterative findings we propose that STAG2 is a clinically significant tumor suppressor in PDA. [ABSTRACT FROM AUTHOR]

The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer. [ABSTRACT FROM AUTHOR]

Cancer cells arise from normal cells through the acquisition of a series of mutations in oncogenes and tumour suppressor genes[SUP1]. Mouse models of human cancer often rely on germline alterations that activate or inactivate genes of interest. One limitation of this approach is that germline mutations might have effects other than somatic mutations, owing to developmental compensation[SUP2,3]. To model sporadic cancers associated with inactivation of the retinoblastoma (RB) tumour suppressor gene in humans, we have produced a conditional allele of the mouse Rb gene. We show here that acute loss of Rb in primary quiescent cells is sufficient for cell cycle entry and has phenotypic consequences different from germline loss of Rb function. This difference is explained in part by functional compensation by the Rb-related gene p107. We also show that acute loss of Rb in senescent cells leads to reversal of the cellular senescence programme. Thus, the use of conditional knockout strategies might refine our understanding of gene function and help to model human cancer more accurately. [ABSTRACT FROM AUTHOR]

Radiation-induced destruction of the hematopoietic system is the primary cause of death based on the findings that transfer of normal bone marrow cells prevents death from lethal irradiation. The stem cell factor-c-kit signaling pathway (SCF/c-kit) has been previously implicated in the hematopoietic recovery which prevents death from lethal irradiation, but the molecular mechanisms that mediate this biological effect are unknown. Since mutations on SCF, c-kit and Slug genes have a similar phenotype in mice, we examined if Slug could complement the radiosensitivity of kit-deficient mice. In this report, we show that Slug acts as a radioprotection agent as lack of Slug results in increased radiosensitivity. This effect cannot be recovered by activating SCF/c-kit in lethally irradiated Slug-deficient mice, as SCF-treated mice did not demonstrate stimulation of hematopoietic recovery leading to survival of the Slug-deficient mice. We found that we could complement the hematopoietic failure in lethally irradiated c-kit-deficient mice by transducing them with a TAT-Slug protein. We conclude that the zinc-finger transcription factor Slug is absolutely necessary for survival from lethal irradiation and identify Slug as the molecular target that mediates the radioprotection through SCF/c-kit. These results indicate that Slug may be a molecular component conferring radioresistance to cancer cells.Oncogene (2003) 22, 4205-4211. doi:10.1038/sj.onc.1206467 [ABSTRACT FROM AUTHOR]

Presents a study that examined the role of the expression of FUS domain in the restoration of liposarcoma development in CHOP-transgenic mice. Components of mesenchymal cancer development; Characteristics of liposarcoma; Information on the FUS-CHOP fusion; Functions of the FUS component of the fusion protein.