Biology subjects

Hany, D.

Publications and source records attributed to Hany, D..

4 recordsLinked to original sources

bioRxiv2023

Hsf1 and the molecular chaperone Hsp90 support a "rewiring stress response" leading to an adaptive cell size increase in chronic stress

Cells are exposed to a wide variety of internal and external stresses. Whereas many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the "rewiring stress response", and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.

cell biology↗

bioRxiv2022

Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer

Breast cancer is a persistent threat to women worldwide. A large proportion of breast cancers are dependent on estrogen receptor (ER) for tumor progression. Therefore, targeting ER with antagonists, such as tamoxifen, remains standard therapy for ER+ breast cancer. The clinical benefits of monotherapy are often counterbalanced by off-target toxicity and development of resistance. Combinations of more than two drugs might be of great therapeutic value to prevent resistance, and to reduce doses, and hence, toxicity. We mined data from the literature and public repositories to construct a network of potential drug targets for synergistic multidrug combinations. With 9 drugs, we performed a phenotypic combinatorial screen with ER+ breast cancer cell lines. We identified two optimized low-dose combinations of 3 and 4 drugs of high therapeutic relevance to the frequent ER+/HER2-/PI3K- mutant subtype of breast cancer. Moreover, we validated the efficacy of the combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft experiments. Thus, we propose multidrug combinations that have the potential to overcome the standard issues of current monotherapies.

cancer biology↗

bioRxiv2022

CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells

In breast cancer, resistance to endocrine therapies that target estrogen receptor (ER), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ER+ breast cancers switch from being estrogen-dependent to -independent remains unclear. With a genome-wide CRISPR/Cas9 knockout screen, we identified new biomarkers and potential therapeutic targets of endocrine resistance. We demonstrate that high levels of PAICS, an enzyme involved in the de novo biosynthesis of purines, can shift the balance of ER activity to be more estrogen-independent and tamoxifen-resistant. We indicate that this is due to an elevated activity of cAMP-activated protein kinase A and mammalian target of rapamycin, kinases known to phosphorylate ER specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxifen-resistant cells to tamoxifen. Based on these findings, we propose the combined targeting of PAICS and ER as a new, effective, and potentially safe therapeutic regimen.

cancer biology↗

bioRxiv2022

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life1, 2. It is involved in multiple branches of proteostasis2, 3, and as a molecular capacitor in morphological evolution4. Although reduced Hsp90 levels cause phenotypic variations5, 6 and correlate with aging7, whether eukaryotic cells and organisms can tune the basal Hsp90 protein levels to alleviate physiologically accumulated stress is unknown. To begin to explore this question, we investigated whether and how mice adapt to the deletion of three out of four alleles encoding cytosolic Hsp90, one Hsp90{beta} allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90{beta} protein to at least wild-type levels. Further mechanistic studies revealed an internal ribosome entry site in the 5UTR of the Hsp90{beta} mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We found that the minimum amount of total Hsp90 that is required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced [≥]100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have been markedly increased during eukaryotic evolution. The incompressible part of the steady-state levels of Hsp90 may have increased to accommodate the ever-growing complexity of the proteome8 on the path towards mammals.

molecular biology↗