bims-stacyt 2019-07-14 papers

Nat Commun. 2019 Jul 11. 10(1): 3055

Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.

Man-Tzu Wang, Nicole Fer, Jacqueline Galeas, Eric A Collisson, Sung Eun Kim, Jeremy Sharib, Frank McCormick.

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.

DOI: https://doi.org/10.1038/s41467-019-11044-9

BMC Cancer. 2019 Jul 12. 19(1): 685

SREBP1 promotes the invasion of colorectal cancer accompanied upregulation of MMP7 expression and NF-κB pathway activation.

Yuyan Gao, Xianxiu Nan, Xinjue Shi, Xiaoqin Mu, Binbin Liu, Huifen Zhu, Bingqing Yao, Xinyi Liu, Tianyue Yang, Yiting Hu, Shulin Liu.

BACKGROUND: Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC).METHODS: Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7.
RESULTS: We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50.
CONCLUSION: Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.

Keywords: CRC; Invasion; MMP7; NF-κB; SREBP1

DOI: https://doi.org/10.1186/s12885-019-5904-x

Int Rev Immunol. 2019 Jul 09. 1-15

Inflammatory processes in obesity: focus on endothelial dysfunction and the role of adipokines as inflammatory mediators.

Manindra Singh, Fabian Benencia.

Obesity predisposes the affected individuals to several metabolic, inflammatory, cardiovascular and malignant pathologies and is a top risk factor for premature mortality. It is now well known that inflammation has a major causative role in obesity-associated disease development and that obesity favors the establishment of a pro-inflammatory milieu at the level of adipose microenvironment. These inflammatory signals result in a disruption of normal cellular-crosstalk between adipose and non-adipose components leading to an altered metabolic and immunological status and a dysfunctional phenotype. Abnormal secretion of adipokines - small adipose-derived signaling molecules - can further assist in the inflammatory processes to offset the adipose tissue towards a dysfunctional state. Although adipokines have been recognized as the link between obesity and pathogenesis, studies are needed to fully understand their mechanism of action and underscore their therapeutic value. Here, we have reviewed obesity-induced metabolic and immunological changes at the level of vasculature and emphasize on the importance of adipokines, particularly leptin, vaspin and visfatin, for their therapeutic relevance.

Keywords: Inflammation; obesity; vaspin leptin; visfatin

DOI: https://doi.org/10.1080/08830185.2019.1638921

J Immunother Cancer. 2019 Jul 12. 7(1): 178

Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade.

Yong-Qiang Chen, Peng-Cheng Li, Ning Pan, Rong Gao, Zhi-Fa Wen, Tian-Yu Zhang, Fang Huang, Fang-Yuan Wu, Xi-Long Ou, Jin-Ping Zhang, Xue-Jun Zhu, Hong-Ming Hu, Kang Chen, Yun-Lang Cai, Li-Xin Wang.

BACKGROUND: CD4+ T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4+ T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4+ T cells in the tumor microenvironment.METHODS: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4+ T cells to examine the function and mechanism of TRAPs in CD4+ T cell differentiation and function. TRAPs-elicited CD4+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model.
RESULTS: Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4+ T cell production of IL-6 via a TLR2-MyD88-NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4+ T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4+ T cells inhibited CD4+ and CD8+ effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4+ T cells markedly retarded tumor growth. Furthermore, B cell or CD4+ T cell depletion impeded tumor growth by increasing effector T cell function.
CONCLUSIONS: HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4+ T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.

Keywords: CD4+ T cell; Extracellular vesicles (EVs); Heat shock protein 90α (HSP90α); IL-6; Regulatory B cell; Tumor-released autophagosome (TRAP)

DOI: https://doi.org/10.1186/s40425-019-0646-5