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. Although 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.

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 α (ERα), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ERα breast cancers switch from being estrogen-dependent to estrogen-independent remains unclear. With a genome-wide CRISPR-Cas9 knockout screen, we identified previously unknown biomarkers and potential therapeutic targets of endocrine resistance.

Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma.

Background: We propose a new approach for designing personalized treatment for colorectal cancer (CRC) patients, by combining ex vivo organoid efficacy testing with mathematical modeling of the results.

Methods: The validated phenotypic approach called Therapeutically Guided Multidrug Optimization (TGMO) was used to identify four low-dose synergistic optimized drug combinations (ODC) in 3D human CRC models of cells that are either sensitive or resistant to first-line CRC chemotherapy (FOLFOXIRI). Our findings were obtained using second order linear regression and adaptive lasso.

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 the estrogen receptor α (ERα) for tumor progression. Therefore, targeting ERα with antagonists, such as tamoxifen, or estrogen deprivation by aromatase inhibitors remain standard therapies for ERα + breast cancer.

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 life. Although reduced Hsp90 levels correlate with aging, it was unknown whether eukaryotic cells and organisms can tune the basal Hsp90 levels to alleviate physiologically accumulated stress. We have investigated whether and how mice adapt to the deletion of three out of four alleles of the two genes encoding cytosolic Hsp90, with one Hsp90β allele being the only remaining one.

Hyperactivation of MAPK Induces Tamoxifen Resistance in SPRED2-Deficient ERα-Positive Breast Cancer.

Breast cancer is the number one cause of cancer-related mortality in women worldwide. Most breast tumors depend on the expression of the estrogen receptor α (ERα) for their growth. For this reason, targeting ERα with antagonists such as tamoxifen is the therapy of choice for most patients.