Identification of Prostate Cancer-Associated MicroRNAs in Circulation Using a Mouse Model of Disease

MicroRNAs (miRNAs) derived from the cell-free fractions of blood are emerging as useful noninvasive markers of cancer. However, many tumors display significant molecular heterogeneity, which is likely to be reflected in the circulating miRNA fingerprints associated with that pathology. One strategy to minimize such heterogeneity is to employ genetically engineered mouse models of human cancer. Here, we describe a method to profile miRNAs in the serum of a mouse model of prostate cancer, TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP), and discuss practical considerations for translating these potential biomarkers into a clinical setting.Luke A. Selth, Scott L. Townley, Joanna L. Gillis, Wayne D. Tilley, and Lisa M. Butle

Primary defect in UVB-induced systemic immunomodulation does not relate to immature or functionally impaired APCs in regional lymph nodes

UVB irradiation of the shaved dorsal skin of mice can cause both local and systemic suppression of contact hypersensitivity responses; the former demonstrated by administration of the sensitizing Ag/hapten to the irradiated site and the latter by its administration at least 72 h later to distal unirradiated sites. The immunological basis of systemic immunomodulation is not clear. When haptens (trinitrochlorobenzene, FITC) were administered to the shaved ventral skin 4 days after irradiation (8 kJ/m(2)) to the shaved dorsum of BALB/c mice, CD11c(+)/FITC(+) cells in the skin-draining lymph nodes from control and irradiated mice produced on a per cell basis similar levels of IL-12 and PGE(2) were phenotypically mature and efficient at presenting FITC to lymphocytes from FITC-sensitized mice. Ag presentation by FACS-sorted CD11c(+) lymph node cells isolated 4 days after UVB irradiation was as efficient as were cells from unirradiated mice at presentation in vitro of an OVA peptide (OVA(323-339)) to CD4(+) cells from OVA-TCR-transgenic DO11.10 mice. Further, IFN-gamma levels were increased in the cultures containing CD11c(+) cells from UVB-irradiated mice, suggesting that inflammation may precede downstream immunosuppression. These results suggest that the primary cause of reduced contact hypersensitivity responses in mice in which UV irradiation and the sensitizing Ag are applied to different sites several days apart must originate from cells other than CD11c(+) APCs that directly or by production of soluble mediators (IL-12, PGE(2)) affect cellular responses in the nodes of UVB-irradiated mice

SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.Magdalene K. Montgomery, Jacqueline Bayliss, Camille Devereux, Ayenachew Bezawork-Geleta ... Scott L. Townley, Luke A. Selth ... et al

Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer

Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies.SignificanceOur study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies.Mohammadreza Alizadeh-Ghodsi ... Lisa M. Butler ... Theresa E. Hickey ... Wayne D. Tilley ... Luke A. Selth ... et al

MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2

Abstract not availableRajdeep Das, Philip A. Gregory, Rayzel C. Fernandes, Iza Denis, Qingqing Wang, Scott L. Townley, Shuang G. Zhao, Adrienne R. Hanson, Marie A. Pickering, Heather K. Armstrong, Noor A. Lokman, Esmaeil Ebrahimie, Elai Davicioni, Robert B. Jenkins, R. Jeffrey Karnes, Ashley E. Ross, Robert B. Den, Eric A. Klein, Kim N. Chi, Hayley S. Ramshaw, Elizabeth D. Williams, Amina Zoubeidi, Gregory J. Goodall, Felix Y. Feng, Lisa M. Butler, Wayne D. Tilley, and Luke A. Selt