The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy

An inflammatory microenvironment, either conferred by an underlying chronic overt or smoldering inflammatory condition constitutes a prerequisite and fuel to essentially all cancers. The complex reciprocal interplay of different cell types in the tumor microenvironment (TME) determines patient outcome. Apart from the actual tumor cells, local and recruited nonmalignant cells as well as the intestinal microbiome actively shape polarization and plasticity of cells in the TME, thereby augmenting protumorigenic and prometastatic inflammatory processes. Here, we address the universality of inflammation in carcinogenesis, review distinct forms of tumor related inflammation and highlight critical processes in the TME actively sustaining a nurturing incubator for cancer progression and therapy resistance. 

Inflammation: the incubator of the tumor microenvironment.

The adipocyte microenvironment and cancer

Abstract The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction. 

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Impaired phosphocreatine metabolism in white adipocytes promotes inflammation

Aberrant hepatic lipid metabolism associated with gut microbiota dysbiosis triggers hepatotoxicity of novel PFOS alternatives in adult zebrafish.

Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.

The MED1 subunit has been shown to mediate ligand-dependent binding of the Mediator coactivator complex to multiple nuclear receptors, including the adipogenic PPARγ, and to play an essential role in ectopic PPARγ-induced adipogenesis of mouse embryonic fibroblasts. However, the precise roles of MED1, and its various domains, at various stages of adipogenesis and in adipose tissue have been unclear. Here, after establishing requirements for MED1, including specific domains, for differentiation of 3T3L1 cells and both primary white and brown preadipocytes, we used multiple genetic approaches to assess requirements for MED1 in adipocyte formation, maintenance, and function in mice. We show that MED1 is indeed essential for the differentiation and/or function of both brown and white adipocytes, as its absence in these cells leads to, respectively, defective brown fat function and lipodystrophy. This work establishes MED1 as an essential transcriptional coactivator that ensures homeostatic functions of adipocytes.

Aarthi V. Maganti

Papers

Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.

Critical roles of transcriptional coactivator MED1 in the formation and function of mouse adipose tissues