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The prevalence of obesity and type II diabetes is growing globally at rates indicating that environment rather than genes is the principal driver. Exposures to high-fat diet and toxicants, as well as micronutrient deficiency, can impact our health and that of future generations. Only now are we beginning to identify mechanisms linking these exposures to parental and offspring health. One connection between environment and health is the epigenome. The epigenome refers to the biochemical content associated with DNA that impacts gene expression and chromatin organization. Uncovering how genomic information is organized and regulated through epigenetic processes to control gene expression and cell functions in the next generation is still in a nascent stage. 

Anne-Sophie Pepin, Christine Lafleur, Romain Lambrot, Vanessa Dumeaux, Sarah Kimmins

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Current Issue

Reprogramming hormone-sensitive prostate cancer to a lethal neuroendocrine cancer lineage by mitochondrial pyruvate carrier (MPC)

Huan Xu, Zhixiao Liu, Dajun Gao, Peizhang Li, ... Zhong Wang

Cell lineage reprogramming is the main approach for cancer cells to acquire drug resistance and escape targeted therapy. The use of potent targeted therapies in cancers has led to the development of highly aggressive carcinoma, including neuroendocrine prostate cancer (NEPC). Although metabolic reprogramming has been reported to be essential for tumor growth and energy production, the relationship between metabolic reprogramming and lineage differentiation which can cause hormone therapy resistance has never been reported in prostate cancer (PCa). Moreover, as there is still no efficient therapy for NEPC, it is urgent to reverse this lineage differentiation during the hormone therapy. Here for the first time, we used in vitro and in vivo human PCa models to study the effect of metabolic reprogramming on the lineage differentiation from the androgen receptor (AR)–dependent adenocarcinoma to AR-independent NEPC. This lineage differentiation leads to antiandrogen drug resistance and tumor development. This phenotype is enabled by the loss of mitochondrial pyruvate carrier (MPC), the gate for mitochondrial pyruvate influx, and can be reversed by MPC overexpression. Morphologic and cellular studies also demonstrate that the pyruvate kinaseM2 (PKM2) involved epithelium–mesenchymal transition process mediated this lineage alteration. Its inhibition is a potential treatment for MPC-lo tumors. All of these results suggest that metabolic rewiring can act as a starter for increased cellular plasticity which leads to antiandrogen therapy resistance through lineage differentiation. This study provides us with a potent treatment target for therapy-induced, enzalutamide-resistant NE-like prostate cancer.

Reprogramming hormone-sensitive prostate cancer to a lethal neuroendocrine cancer lineage by mitochondrial pyruvate carrier (MPC)

Huan Xu, Zhixiao Liu, Dajun Gao, Peizhang Li, ... Zhong Wang

Cell lineage reprogramming is the main approach for cancer cells to acquire drug resistance and escape targeted therapy. The use of potent targeted therapies in cancers has led to the development of highly aggressive carcinoma, including neuroendocrine prostate cancer (NEPC). Although metabolic reprogramming has been reported to be essential for tumor growth and energy production, the relationship between metabolic reprogramming and lineage differentiation which can cause hormone therapy resistance has never been reported in prostate cancer (PCa). Moreover, as there is still no efficient therapy for NEPC, it is urgent to reverse this lineage differentiation during the hormone therapy. Here for the first time, we used in vitro and in vivo human PCa models to study the effect of metabolic reprogramming on the lineage differentiation from the androgen receptor (AR)–dependent adenocarcinoma to AR-independent NEPC. This lineage differentiation leads to antiandrogen drug resistance and tumor development. This phenotype is enabled by the loss of mitochondrial pyruvate carrier (MPC), the gate for mitochondrial pyruvate influx, and can be reversed by MPC overexpression. Morphologic and cellular studies also demonstrate that the pyruvate kinaseM2 (PKM2) involved epithelium–mesenchymal transition process mediated this lineage alteration. Its inhibition is a potential treatment for MPC-lo tumors. All of these results suggest that metabolic rewiring can act as a starter for increased cellular plasticity which leads to antiandrogen therapy resistance through lineage differentiation. This study provides us with a potent treatment target for therapy-induced, enzalutamide-resistant NE-like prostate cancer.

2021 impact factor: 7.422

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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