Obesity is a major public health concern at the origin of many pathologies, including cancers. Among them, the incidence of gastro-intestinal tract cancers is significantly increased, as well as the one of hormone-dependent cancers. The metabolic changes caused by overweight mainly with the development of adipose tissue (AT), insulin resistance and chronic inflammation induce hormonal and/or growth factor imbalances, which impact cell proliferation and differentiation. AT is now considered as the main internal source of endocrine disrupting chemicals (EDCs) representing a low level systemic chronic exposure. Some EDCs are non-metabolizable and can accumulate in AT for a long time. We are chronically exposed to low doses of EDCs able to interfere with the endocrine metabolism of the body. Importantly, several EDCs have been involved in the genesis of obesity affecting profoundly the physiology of AT. In parallel, EDCs have been implicated in the development of cancers, in particular hormone-dependent cancers (prostate, testis, breast, endometrium, thyroid). While it is now well established that AT secretes adipocytokines that promote tumor progression, it is less clear whether they can initiate cancer. Therefore, it is important to better understand the effects of EDCs, and to investigate the buffering effect of AT in the context of progression but also initiation of cancer cells using adequate models recommended to uncover and validate these mechanisms for humans. We will review and argument here the potential role of AT as a crosstalk between EDCs and hormone-dependent cancer development, and how to assess it.

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Genome engineering has become more accessible thanks to the RNA programmable endonucleases such as the CRISPR/Cas9 system. However, using this editing technology in synthetic organs called ‘organoids’ is still very inefficient. This is due to the delivery methods used for the CRISPR-Cas9 machinery, which include electroporation of CRISPR/Cas9 DNA, mRNA or ribonucleoproteins (RNPs) containing the CAS9-gRNA complex. However, these procedures are toxic to some extent for the organoids. Here we describe the use of the ‘Nanoblade’ technology, which outperformed by far knock-out (KO) levels achieved to date by gene editing in murine and human tissue derived organoids. We reached up to 80% of gene KO in organoids after treatment with nanoblades. Indeed, high-level nanoblade-mediated KO for the androgen receptor (AR) encoding gene and the cystic fibrosis transmembrane conductance regulator (CFTR) gene was achieved with single gRNA or dual gRNA containing nanoblades in murine prostate and colon organoids. Likewise, nanoblades achieved high levels of gene editing in human organoids ranging between 20% and 50%.Most importantly, in contrast to other gene editing methods, this was obtained without toxicity for the organoids. Only four weeks are required to obtain stable gene KO in organoids and nanoblades simplify and allow rapid genome editing in organoids with little to no side-effects such as possible unwanted INDELS in off-target sites.

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