News & Views in 2016

Micronucleation of missegregated chromatin can lead to substantial chromosome rearrangements via chromothripsis. However, the molecular details of micronucleus-based chromothripsis are still unclear. Now, an elegant system that specifically induces missegregation of the Y chromosome provides insight into this process, including a role for non-homologous end joining.

Cadherin adhesion complexes have recently emerged as sensors of tissue tension that regulate key developmental processes. Super-resolution microscopy experiments now unravel the spatial organization of the interface between cadherins and the actin cytoskeleton and reveal how vinculin, a central component in cadherin mechanotransduction, is regulated by mechanical and biochemical signals.

Delineating the behaviour of haematopoietic stem cells (HSCs) in vivo has thus far proven challenging. Two studies in zebrafish and mouse models now track HSCs in vivo using fate mapping with multicolour approaches to provide further insights into clonal events that regulate blood development, HSC function and differentiation during homeostasis and stress conditions.

Many cell types in our body move in a collective manner, which requires individual cells to align their movements relative to that of their neighbours. A mechanism is now described in which cadherin-rich protrusions are extended from leading migrating cells and engulfed by follower cells to guide collective migration.

Despite being one of the most studied signalling pathways, precisely how phospholipid synthesis is regulated in the phosphoinositide signalling cascade remains unclear. The scaffold protein IQGAP1 is now shown to orchestrate the assembly of a multi-enzyme complex that streamlines PtdIns(3,4,5)P₃ synthesis to facilitate Akt activation in response to extracellular stimuli.

Work from the early 1980s reported strange lobes protruding from Caenorhabditis elegans germ cell precursors. However, the fate and potential significance of these lobes remained unexplored for decades. Now, neighbouring endodermal cells are shown to sever and digest these lobes, in an unexpected process of 'intercellular cannibalism', which could play an important part in regulating primordial germ cells.

Embryonic stem cells maintain pluripotency through countless mitoses. A recent report shows that the transcription factor Esrrb remains bound to chromatin during mitosis, including at regulatory regions that support pluripotency. Mitotic chromatin occupancy by Esrrb might stabilize the defining transcriptional programmes of embryonic stem cells through cell division.

Two studies now show that Ewing's tumour-associated antigen 1 (ETAA1) is recruited to sites of DNA replication stress through its interaction with replication protein A, where it stimulates the ATR kinase to promote efficient genome duplication. These findings provide exciting insight into the already very complex regulatory mechanism of the ATR activation cascade.

It is well established that mutant forms of the p53 tumour suppressor acquire pro-oncogenic activities. Inhibition of the mevalonate pathway is now shown to promote degradation of select oncogenic mutant p53 proteins, indicating that destabilization of mutant p53 could be a promising therapeutic strategy.

The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, and its size needs to be carefully controlled. Downsizing the ER by autophagy is now shown to involve Sec62, a protein that also helps to build up the organelle. This link suggests a molecular switch for ER size control.

Lysosomes are digestive organelles of the endocytic and autophagic pathways. Increasing lysosome enzyme activities could help to clear pathological cellular waste. A recent study shows that lysosomal digestive functions can be promoted in isolated cells and mice by pharmacologically stimulating the autophagy- and lysosome-regulating transcription factors TFEB and ZKSCAN3 through previously unrecognized mTORC1-independent pathways acting via PKC.

Limited perfusion of solid tumours produces a nutrient-deprived tumour core microenvironment. Low glutamine levels in the tumour core are now shown to lead to reduced levels of α-ketoglutarate and decreased histone demethylase activity, thereby promoting a less differentiated and more therapy-resistant state of the tumour cells.

While the beneficial versus detrimental implications of the senescence-associated secretome remain an issue of debate, time-resolved analyses of its composition, regulatory mechanisms and functional consequences have been largely missing. The dynamic activity of NOTCH is now shown to direct two distinct senescence phenotypes, by first promoting a pro-senescent TGF-β1-dependent secretome, followed by a second wave of pro-inflammatory, senescence-clearing cytokines.

Extracellular vesicles, such as exosomes, are important effectors in the formation of tumour-fostering niches. Pigmented melanosomes are now shown to have a relevant role in establishing a tumour niche in primary melanoma by reprogramming dermal fibroblasts into cancer-associated fibroblasts through the transfer of miR-211.

The Hippo pathway is a key regulator of organ size that has also been implicated in tumorigenesis. Yap, one of the effectors of Hippo signalling, is now reported to support these functions by promoting glutamine synthesis.

p53 mutations occur very frequently in human cancer. Besides abrogating the tumour suppressive functions of wild-type p53, many of those mutations also acquire oncogenic gain-of-function activities. Augmentation of proteasome activity is now reported as a common gain-of-function mechanism shared by different p53 mutants, which promotes cancer resistance to proteasome inhibitors.

Clearing misfolded proteins from the cytoplasm is essential to maintain cellular homeostasis. Now, a parallel clearance system is described that uses the deubiquitylase USP19 to enable secretion of misfolded cytoplasmic proteins when conventional proteasomal degradation is compromised. Misfolding-associated protein secretion (MAPS) has important implications for protein quality control and prion-like transmission.

During development, tubular networks form through the joining of lumenized branches. Further insights into tracheal tube fusion in Drosophila melanogaster now reveal the molecular steps that promote the connection of two apical membrane compartments within a single cell through secretory lysosomes.

Although known to induce cellular senescence, an important tumour suppressor mechanism, mutation of CDKN1A — the gene encoding p21 (also known as WAF1 or CIP1) — is rare in human cancers. Now, a study reports a previously unappreciated oncogenic effect of p21 overexpression that shapes cancer genome evolution through induction of replication stress.

Tumour-associated macrophages facilitate cancer progression, but whether they can be reprogrammed to elicit an anti-tumour response remains unclear. Deletion of the microRNA-processing enzyme Dicer is now shown to rewire macrophages to an anti-tumour mode, leading to an enhanced response to immunotherapy and inhibition of tumour progression.