Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase-associated protein SIN3B is essential for oncogeneinduced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1α. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis.

Forkhead FoxO transcription factors exert critical biological functions in response to genotoxic stress. In mammals four FoxOs proteins are known. FoxOs induce cell cycle arrest, repair damaged DNA, or initiate apoptosis by modulating genes that control these processes. In particular, FoxO proteins are critical regulators of oxidative stress by modulating the expression of several anti-oxidant enzyme genes. This function of FoxO is essential for the regulation of stem and progenitor cell pool in the hematopoietic system and possibly other stem cells. Overall functions of FoxOs are consistent with their role as tumor suppressors as has been shown in animal models. As such, FoxOs are suppressed in various cancer cells. However, recent reports strongly suggest that FoxOs are critical for the maintenance of leukemic stem cells. The diverse functions of FoxOs are orchestrated by tight regulations of expression and activity of its family members. Here we discuss the recent progress in understanding the function of FoxOs specifically in normal and cancer stem cells and what is known about the regulation of these proteins in various cell types and tissues including in the physiological setting of primary cells in vivo. These studies underscore the importance of regulation of FoxO proteins and whether these factors play distinct or redundant functions. Understanding how FoxOs are modulated is critical for devising novel therapies based on targeted restoration/or inhibition of FoxO function in cancer and in other diseased cells in which FoxOs have a key function.

The trophoblast is a supportive tissue in mammals that plays key roles in embryonic patterning, foetal growth and nutrition. It shows an extensive growth up to the formation of the placenta. This growth is believed to be fed by trophoblast stem cells able to self-renew and to give rise to the differentiated derivatives present in the placenta. In this review, we summarize recent data on the molecular regulation of the trophoblast in vivo and in vitro. Most data have been obtained in the mouse, however, whenever relevant, we compare this model to other mammals. In ungulates, the growth of the trophoblast displays some striking features that make these species interesting alternative models for the study of trophoblast development. After the transfer of somatic nuclei into oocytes, studies in the mouse and the cow have both underlined that the trophoblast may be a direct target of reprogramming defects and that its growth seems specifically affected. We propose that the study of TS cells derived from nuclear transfer embryos may help to unravel some of the epigenetic abnormalities which occur therein.

Development after nuclear transfer (NT) is subjected to defects originating from both the epiblast and the trophoblast parts of the conceptus and is always accompanied by placentomegaly at term. Here we have investigated the origin of the reprogramming errors affecting the trophoblast lineage in mouse NT embryos. We show that trophoblast stem (TS) cells can be derived from NT embryos (ntTS cells) and used as an experimental in vitro model of trophoblast proliferation and differentiation. Strikingly, TS derivation is more efficient from NT embryos than from controls and ntTS cells exhibit a growth advantage over control TS cells under self-renewal conditions. While epiblast-produced growth factors Fgf4 and Activin exert a fine-tuned control on the balance between self-renewal and differentiation of control TS cells, ntTS cells exhibit a reduced dependency upon their micro-environment. Since the supply of growth factors is known do decrease at the onset of placental formation in vivo we propose that TS cells in NT embryos continue to self-renew during a longer period of time than in fertilized embryo. The resulting increased pool of progenitors could contribute to the enlarged extra-embryonic region observed in the early trophoblast of in vivo grown mouse NT blastocysts that results in placentomegaly.