Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

Summary Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.

The root is the organ responsible for the uptake of water and therefore has a very important role in drought tolerance. The aims of the present work were to characterize nine traits of the root system architecture (RSA) and the shoot dry weight (W) of twelve genotypes of Brachypodium spp. under water stress and to establish the relationship between RSA phenotyping traits and SSRs. Two culture media, one standard (SM) and one (PEG) to induced water stress have been used. In SM medium, B. stacei had the highest values of W and all the RSA traits, except the mean diameter of the seminal roots, followed by B. hybridum and B. distachyon. In the PEG medium, root length increased in B. distachyon, decreased in B. hybridum and remained the same in B. stacei. A two-way hierarchical cluster analysis from 117 polymorphic SSRs and the traits of the RSA of the Brachypodium spp. genotypes, was performed. Brachypodium genotypes were separated into three groups corresponding to each species. In the second way of the hierarchical clustering association were observed between five RSA variables and SSR markers, which could be useful in the search for genes or QTLs related to RSA characters.