Herd immunity for tumor cells

Transmissible endoplasmic reticulum stress (TERS) can spread from one cancer to another and convey resistance to many treatments, including nutrient starvation, the chemotherapy Taxol (paclitaxel) and the proteasome inhibitor Velcade (bortezomib, Takeda Pharmaceutical Co. Ltd.). Researchers at the University of California at San Diego had previously shown that the unfolded protein response, a reaction to cellular stress, could be transmitted from cancer cells to bone marrow cells. In the new studies, they showed that the response could also be transmitted from one cancer cell to another. When implanted into mice, TERS-primed cancer cells gave rise to faster growing tumors than did vehicle-primed cancer cells. "Collectively, our data demonstrate that TERS is a mechanism of intercellular communication through which tumor cells can adapt to stressful environments," the authors concluded. They published their results in the June 6, 2017, issue of Science Signaling.

Microglial subtype fights AD

Researchers have identified a new kind of microglia that was associated with neurodegeneration and able to take up amyloid beta, suggesting a functional role in fighting neurodegenerative processes. There are conflicting studies with respect to the net effect of microglia, which are brain immune cells, on the progression of neurodegeneration. Overall, microglia are associated with inflammation, which would enhance progression, but singe-cell analyses have suggested that there might be protective subtypes. A team from the Israeli Weizmann Institute analyzed individual microglia in mouse models of Alzheimer's disease using RNA sequencing and identified a novel subtype of protective microglia, disease-associated microglia (DAM). The team further showed that the gene expression and signaling dynamics changed as the disease progressed. "Our work establishes a new experimental and conceptual paradigm to accurately analyze the involvement of the immune system in neurodegeneration and other brain pathologies," the authors concluded. They published their findings in the June 8, 2017, online issue of Cell.

Cell cycle proteins control metabolism

Progression through the cell cycle is controlled by a group of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Metabolism and the cell cycle are functionally linked by the need for metabolites to grow. Now, researchers from the Dana-Farber Cancer Institute have shown that cyclin D3 and CDK6 form complexes that directly affect metabolism. "We propose that measuring the levels of cyclin D3–CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon inhibition of CDK4 and CDK6. Cyclin D3–CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anticancer therapy," the authors wrote. Their work appeared in the June 8, 2017, issue of Nature.

Broadening Cpf1's horizons

Cpf1 is a bacterial nuclease that can be used as part of CRISPR gene editing systems, and because it makes an overhanging rather than a blunt cut to DNA it can be used in applications where Cas9 is not a suitable choice. However, the motif that Cpf1 needs to bind to DNA sequences limits its utility. Researchers from The Broad Institute have engineered Cpf1 nucleases from two different bacterial species to make them recognize a broader range of motifs than their natural counterparts. The resulting nucleases were tested in human cells and shown to have enhanced on-target activity, while their off-target activity was not increased. The team estimated that "together, these variants increase the targeting range of Cpf1 by approximately threefold in human coding sequences." They published their results in the June 5, 2017, online issue of Nature Biotechnology.

Tissue agnostic tumor testing

In May, the FDA approved Keytruda (pembrolizumab, Merck & Co. Inc.) in patients with mismatch repair-deficient tumors, the first approval that was independent of a tumor's anatomical origin. Researchers from Memorial Sloan-Kettering Cancer Center have published the details of one of the studies the approval was based on. They reported data from 86 patients with MMR-deficient tumors who were treated with Keytruda. They showed an overall response rate of 53 percent, with 12 percent of patients having complete responses. Mismatch repair-deficient tumors have an extremely high number of mutations, providing a cornucopia of neoantigens that the patients can mount an immune response to. In a genome sequencing study of roughly 12,000 tumors, the authors showed that MMR-deficient tumors made up roughly 8 percent of stage I to III cancers, and 4 percent of stage IV cancers, which together account for 60,000 cancers in the U.S. "Because genetic and immunohistochemical tests for MMR deficiency are already widely available, these results tie immunity, cancer genetics, and therapeutics together in a manner that will likely establish a new standard of care," the authors concluded. Their work appeared in the June 8, 2017, online issue of Science.