Leslie K. Ferrarelli

Why pain and stress lead to depression

Neuroscience Chronic stress or pain is associated with the development of depression. Descalzi et al. examined gene expression changes in the brain in mouse models of nerve injury– or chronic stress–induced depression. They found some common changes in the expression of genes encoding signaling

Locking TNFR2 to kill ovarian cancer

Cancer Immunotherapy The TNF (tumor necrosis factor) ligand family promotes tumor growth and progression. Torrey et al. developed an antibody that locks TNFR2, a TNF receptor found on immunosuppressive regulatory T cells and some tumor cells, in an inactive state (see the Focus by Chen and Oppenheim). The antibody inhibited the proliferation of regulatory T cells while promoting the proliferation of effector T cells isolated from metastatic sites in ovarian cancer patients. The antibody had less of an effect on T cells from normal donors. Thus, this antibody may be more specific and less toxic than current antibodies against TNFRs. Sci. Signal. 10 , eaaf8608, eaal2328 (2017).

Melanoma cells talk to keratinocytes

Cancer Although identifying cancer-driving mutations is important, therapeutics usually target proteins, and tumor progression is affected by nearby cells. Ostalecki et al. performed protein profiling in skin samples from human melanoma patients. They observed changes in the levels and subcellular localization of proteins in melanocytes and keratinocytes that were associated with various stages of melanoma development. Early-stage melanoma cells transferred a pair of proteins to adjacent normal keratinocytes, leading to altered protein levels and secretion. Inhibiting this intercellular communication might be therapeutically beneficial for melanoma patients. Sci. Signal. 10 , eaai8288 (2017).

Inflammatory decoy control

Sepsis Bacterial infection can lead to sepsis, inflammation, and death. Li et al. found that the long noncoding RNA MEG3-4 and the mRNA encoding the proinflammatory cytokine interleukin-1β (IL-1β) competitively bound to the microRNA miR-138 in the lungs of bacterially infected mice. Initially,

Kinase networks in inflammation

Rheumatoid Arthritis Although inflammation in rheumatoid arthritis is driven by the increased activity of p38, inhibitors of this kinase are ineffective in patients. Using synovial fibroblasts and fluid from rheumatoid arthritis patients, Jones et al. found that p38 mediated negative cross-talk to

Channeling metastasis pain with VEGF

Pain Metastatic cancer in the bone is painful. Yang et al. found that vascular endothelial growth factor (VEGF) promotes tumor angiogenesis and also contributes to this pain. In a rat model of bone-metastatic breast cancer, tumor-secreted VEGF repressed the expression of the potassium (K+) channel TRESK. Loss of K+ current through TRESK increased the excitability of sensory neurons and made the animals hypersensitive to heat and touch near the bone lesion. Blocking this pathway restored channel activity and alleviated pain. Sci. Signal. 11 , eaao5150 (2018).

An alternative treatment for leukemia

Leukemia In some acute myeloid and juvenile myelomonocytic leukemias (AMLs and JMMLs), tumor growth is driven by activating mutations in the phosphatase PTPN11. Jenkins et al. found that mutant PTPN11 activity is enhanced by the kinase TNK2. The multikinase inhibitor dasatinib decreased TNK2 and

Fat, microRNAs, and liver disease

Fatty Liver Disease Obesity and high-fat diets are linked to fatty liver disease. One hallmark of disease is repression of the cell-stress protein IRE1α. In livers from mice fed a high-fat diet and from patients with hepatic steatosis, Wang et al. found that IRE1α activity was repressed because of

A primitive role for ATF6

Development The unfolded protein response (UPR) preserves endoplasmic reticulum (ER) homeostasis in mature cells. However, inactivating mutations in the UPR-associated transcription factor ATF6 cause congenital vision defects, suggesting a developmental role for ATF6 as well. Kroeger et al. found

Modeling chemotherapy-drug combinations

Cancer Therapy Pharmacological inhibitors of DNA repair pathways can enhance the efficacy of chemotherapy. Alkan et al. modeled cancer cell responses to various chemotherapies and tested the efficacy of combining chemotherapy with DNA repair inhibition. In addition to the expected synergy between chemotherapy and an inhibitor of ATR (a DNA repair pathway kinase) in cultured cells and in vivo, there were some unexpected differences in outcome when applying low-versus high-dose chemotherapy regimens. Thus, modeling in cells can help inform therapeutic development. Sci. Signal. 11 , eaat0229 (2018).