Vergato, C. | bioRxiv Science

bioRxiv2022

Constitutively active STAT5b feminizes mouse liver gene expression

STAT5 is an essential transcriptional regulator of the sex-biased actions of growth hormone (GH) in the liver. Delivery of constitutively active STAT5 (STAT5CA) to male mouse liver using an engineered adeno-associated virus with high tropism for the liver is shown to induce widespread feminization of the liver, with extensive induction of female-biased genes and repression of male-biased genes, largely mimicking results obtained when male mice are given GH as a continuous infusion. Many of the gene expression changes observed were associated with STAT5 binding to liver chromatin, supporting the proposed direct role of persistently active STAT5 in continuous GH-induced liver feminization. The feminizing effects of STAT5CA were dose-dependent; moreover, at higher levels, overexpression of STAT5CA resulted in some histopathology not seen in continuous GH-infused male liver, including hepatocyte hyperplasia and distorted liver architecture. These findings establish that the persistent activation of STAT5 by GH that characterizes female liver is by itself sufficient to account for the female-biased expression of a majority of female-biased genes. Moreover, histological changes seen when STAT5CA is overexpressed highlight the importance of carefully evaluating such effects before considering such STAT5 derivatives for therapeutic use in treating liver disease.

genomics↗

bioRxiv2021

Type-I interferon signaling is essential for robust metronomic chemo-immunogenic tumor regression in murine triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by poor prognosis and aggressive growth, with limited therapeutic options for many patients. Here, we use two syngeneic mouse TNBC models, 4T1 and E0771, to investigate the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I interferon (IFN) signaling to therapeutic activity. Chemically-activated cyclophosphamide induced robust IFN/{beta} receptor-1-dependent signaling linked to hundreds of IFN-stimulated gene responses in both TNBC lines. Further, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by extensive downstream gene responses, robust immune cell infiltration and prolonged tumor regression. The immune dependence of these effective anti-tumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFN/{beta} receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these TNBC tumors to cyclophosphamide administered on a metronomic schedule. SignificanceTNBC has poor prognosis and few therapeutic options. We show that cyclophosphamide treatment can induces extensive tumor regression in syngeneic mouse models of TNBC via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust anti-tumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving TNBC treatment efficacy.

cancer biology↗