Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression

International audienceMetabolic heterogeneity within the tumor microenvironment promotes cancercell growth and immune suppression. We determined the impact of mitochondria-targeted complex I inhibitors (Mito-CI) in melanoma. Mito-CI decreased mitochondria complex I oxygen consumption, Akt-FOXO signaling, blocked cell cycleprogression, melanoma cell proliferation and tumor progression in an immunecompetent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within andhalted tumor cell proliferation, it also elevated infiltration of activated effectorT cells and decreased myeloid-derived suppressor cells (MDSC) as well as tumor-associated macrophages (TAM) in melanoma tumors in vivo. Anti-proliferative doses of Mito-CI inhibited differentiation, viability, and the suppressive function of bone marrow-derived MDSC and increased proliferation-independentactivation of T cells. These data indicate that targeted inhibition of complex Ihas synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling

Avaliação das carcaças de novilhos F1 Angus-Nelore em pastagens de Brachiaria decumbens submetidos a diferentes regimes alimentares Carcass evaluation of F1 Angus-Nellore steers on Brachiaria decumbens pasture under different feeding regimes

O experimento foi conduzido no Centro Nacional de Gado de Corte da Empresa Brasileira de Pesquisa Agropecuária (Embrapa Gado de Corte). Foram utilizados 45 novilhos F1 Aberdeen Angus-Nelore para avaliar o efeito de diferentes regimes alimentares, nos períodos secos da recria/terminação, sobre as características de carcaça. Os tratamentos aplicados foram: testemunha, sem suplementação (S/S); suplementação na 2ª seca (S2S); suplementação na 1ª seca (S1S); suplementação nas duas secas (S12S) e suplementação na 1ª seca e confinamento na 2ª (S1C2). Os animais foram abatidos com pesos entre 460 e 480 kg. O efeito dos tratamentos foi avaliado pelo método dos quadrados mínimos. Animais com melhor nível nutricional na 2ª seca (S1C2, S2S e S12S) apresentaram melhor rendimento de carcaça e maiores pesos de carcaça quente e fria do que aqueles suplementados somente na 1ª seca ou não suplementados. A suplementação somente na 1ª seca produziu carcaças semelhantes, em todos os aspectos avaliados, às do tratamento testemunha. Conclui-se que melhorar o nível alimentar na 2ª seca da vida do animal é fundamental para aumentar o rendimento de carcaça. Suplementação na 1ª seca, como prática isolada, não contribui para o rendimento e qualidade da carcaça.<br>This trial was conducted at National Beef Cattle Research Center of Brazilian Agricultural Research Corporation (Embrapa Beef Cattle). Forty five F1 Aberdeen Angus-Nellore steers were used to evaluate the effects of different dry seasons feeding schemes on carcass characteristics. The treatments were: control, without supplementation (S/S); supplementation in 2nd dry period (S2S); supplementation in 1st dry period (S1S); supplementation in 1st and 2nd dry periods (S12S) and supplementation in 1st dry period and confinament in 2nd one (S1C2). Animals were slaughtered at 460-480 kg of live weight and the treatments effects were evaluated by least square means. Steers with higher nutritional levels in 2nd dry season (S1C2; S2S; S12S) showed more dressing percentage and higher hot and cold carcass weights than those supplemented only in 1st dry period or non supplemented. Animals supplemented only in 1st dry season showed similar carcasses than non supplemented. It was concluded that increasing the 2nd dry season nutritional level is primary to expand the dressing percentage. Supplementation in 1st dry period solitarily does not affect dressing percentage neither carcass quality

Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment. EXPERIMENTAL DESIGN: We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC. RESULTS: We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression. CONCLUSIONS: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment