Research Highlights in 2016

Robust genetic evidence in mice and humans indicates that RANK signaling plays a major role in mammary carcinogenesis driven by BRCA1/BRCA2 mutations. These findings may inaugurate a new era of breast cancer prevention, changing the life of millions of women worldwide.

Hematopoietic stem cells (HSCs) sponsoring hematopoiesis are preserved in the bone marrow (BM) microenvironment or niche. Here, Itkin et al. demonstrate how distinct blood vessels contribute to HSC maintenance and hematopoiesis in the BM niches.

Root meristem growth factors (RGFs), a family of “orphan” peptides, control root growth by altering the expression and gradient of transcription factors PLETHORAS (PLTs) that maintain stem cell niche. However, the receptors for RGFs remain unknown until recently when three groups independently reported the identification of a group of receptor-like kinases (RLKs) as cell surface receptors for RGFs.

The autophagy-related process LC3-Associated Phagocytosis, or LAP, is known to control the degradation of engulfed cells and microorganisms. Now Martinez et al. discover that LAP controls immune responses to dying cells and its inhibition leads to development of Systemic Lupus Erythematosus-like disease.

Changing exposure to intestinal helminths, or alterations in our intestinal microbiome, have been independently proposed to underlie the increasing incidence of chronic inflammatory diseases including allergy, autoimmunity and inflammatory bowel disease (IBD) observed in developed nations. A recent study in Science links these findings by showing that intestinal helminth infection can prevent the outgrowth of a common intestinal bacterium that causes IBD in genetically susceptible mice.

The non-canonical inflammasome triggers host cell death and inflammation upon recognition of cytosolic LPS. A recent report in Cell now shows that Outer Membrane Vesicles (OMVs) of extracellular Gram-negative bacteria can deliver LPS into the host cell cytosol.

The current outbreak of Zika virus-associated diseases in South America and its threat to spread to other parts of the world has emerged as a global health emergency. Insights from cell and animal models to understand how Zika virus causes severe birth defects may lead to treatments and prevention of these diseases.

Circadian rhythms in the level of intracellular Mg²⁺ appear to be widely conserved phylogenetically, and have the potential to impact nearly all aspects of metabolism. Moreover, the clock regulates the ion channels that generate the rhythm, demonstrating that the whole cell operates as a circadian system.

Whether mixed lineage kinase domain-like (MLKL) mediates necroptosis by forming ion channel, none-selective pore, or simply by disrupting plasma membrane is unclear. In a paper published in recent issue of Cell Research, Xia et al. showed that MLKL functions as a novel class of cation channel.

Detachment from extracellular matrix causes metabolic defects that transformed cells must overcome in order to survive and proliferate outside of their normal niche. A recent report from Jiang et al. published in Nature describes how cancer cells grown in suspension utilize reductive carboxylation of glutamine to transfer reducing power from the cytosol to mitochondria to detoxify reactive oxygen species and promote anchorage-independent growth and survival.

Asymmetric division in CD8 T cells produces two daughter cells expressing different levels of c-Myc with distinct metabolic profiles. Manipulating this asymmetric partitioning of c-Myc skews T cell responses and potentially allows the development of more effective vaccines and cancer immunotherapies.

Mechanical deformability is known to increase during cancer progression. Now Ma et al. identify a therapeutic strategy that targets deformable cells by microparticle-based drug delivery.

Rupture of the nuclear envelope (NE) during interphase is thought to be an infrequent event in healthy cells. Two papers recently published in Science describe the transient disruption of the NE continuity in cells migrating through confined spaces, and uncover an essential role for the Endosomal Sorting Complex Required for Transport (ESCRT) machinery in the resealing of these nuclear discontinuities.

DROSHA and its partner DGCR8 form a heterotrimeric complex named Microprocessor, which is essential for microRNA biogenesis. A recent study by Kwon et al. in Cell reveals the structure of a DROSHA construct in complex with the C-terminal region of DGCR8, thereby unveiling the topology and interactions between components of the Microprocessor and insights into its 'ruler'-based cleavage activity and function.

For decades, MYC has been known for its role in regulating cancer cell proliferation and survival. In a recent paper published in Science, Casey et al. have uncovered a new function for MYC in promoting immune evasion by directly regulating expression of programmed death-ligand 1 (PD-L1) and CD47 on cancer cells.

In a recent paper in Cell Research, Yu et al. show that maternally inherited Yes-associated protein (Yap), a co-activator of TEAD family transcription factors, plays a key role in activating embryonic transcription following fertilization in the mouse.

Wnt morphogens are notoriously elusive proteins. Thanks to a recent study published in Nature, Clevers and colleagues give us a first glimpse of a mammalian Wnt in action in the gut epithelium.

Toll-Like Receptors (TLRs) play critical roles in the early innate immune response to invading pathogens by sensing microorganisms; a number of accessory molecules have been shown to assist microbial recognition by TLRs. In a recent paper in Cell Research, Yang et al. demonstrate that Mex3B is associated with TLR3 in the endosomes and promotes dsRNA binding and proteolytic processing of TLR3, suggesting that Mex3B acts as a coreceptor of TLR3 in response to dsRNA.

A novel approach to gene correction by genome editing shows great promise as a treatment for Duchenne muscular dystrophy (DMD). CRISPR/Cas9 delivered by adeno-associated virus to a mouse model for DMD demonstrated improvement in function and histology.

Non-genetic inheritance is an evocative topic; in the past few years, the debate around potential inheritance of life-time experiences independent of social factors in mammals has become highly prominent due to increasing evidence for phenotypes in the offspring after paternal environmental exposures. Strikingly, two independent studies published in Science newly implicate a special class of RNA, transfer RNA fragments, in the intergenerational effects of paternal dietary intervention.