Ral GTPases promote metastasis by controlling biogenesis and organ colonization of exosomes

Cancer extracellular vesicles (EVs) mainly exert pro-tumoral functions by changing the phenotypes of stromal cells to the benefit of tumor growth and metastasis. They shuttle to distant organs and fertilize pre-metastatic niches facilitating subsequent seeding by circulating tumor cells. The levels of tumor secreted EVs correlate with tumor aggressiveness, however, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Here, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and thereby tune the biogenesis and secretion of pro-metastatic EVs. RalA and RalB promote lung metastasis in a syngeneic mouse model. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and, as a consequence, are less efficient in promoting lung metastasis. RalA or RalB modulate the EV levels of the adhesion molecule MCAM/CD146, which mediates lung colonization. Finally, RalA and RalB, but also MCAM/CD146, are factors of poor prognosis in human breast cancer patients. Altogether, our study identifies Ral GTPases as central molecules linking the mechanisms of EVs secretion, cargo loading to their capacity to disseminate and induce pre-metastatic niches.

A hybrid sub-lineage of Listeria monocytogenes comprising hypervirulent isolates

The foodborne pathogen Listeria monocytogenes (Lm) is a highly heterogeneous species and currently comprises of 4 evolutionarily distinct lineages. Here, we characterize isolates from severe ovine listeriosis outbreaks that represent a hybrid sub-lineage of the major lineage II (HSL-II) and serotype 4h. HSL-II isolates are highly virulent and exhibit higher organ colonization capacities than well-characterized hypervirulent strains of Lm in an orogastric mouse infection model. The isolates harbour both the Lm Pathogenicity Island (LIPI)-1 and a truncated LIPI-2 locus, encoding sphingomyelinase (SmcL), a virulence factor required for invasion and bacterial translocation from the gut, and other non-contiguous chromosomal segments from another pathogenic species, L. ivanovii. HSL-II isolates exhibit a unique wall teichoic acid (WTA) structure essential for resistance to antimicrobial peptides, bacterial invasion and virulence. The discovery of isolates harbouring pan-species virulence genes of the genus Listeria warrants global efforts to identify further hypervirulent lineages of Lm.

Critical symbiont signals drive both local and systemic changes in diel and developmental host gene expression

The colonization of an animal’s tissues by its microbial partners creates networks of communication across the host’s body. We used the natural binary light-organ symbiosis between the squidEuprymna scolopesand its luminous bacterial partner,Vibrio fischeri, to define the impact of colonization on transcriptomic networks in the host. A night-active predator,E. scolopescoordinates the bioluminescence of its symbiont with visual cues from the environment to camouflage against moon and starlight. Like mammals, this symbiosis has a complex developmental program and a strong day/night rhythm. We determined how symbiont colonization impacted gene expression in the light organ itself, as well as in two anatomically remote organs: the eye and gill. While the overall transcriptional signature of light organ and gill were more alike, the impact of symbiosis was most pronounced and similar in light organ and eye, both in juvenile and adult animals. Furthermore, the presence of a symbiosis drove daily rhythms of transcription within all three organs. Finally, a single mutation inV. fischeri—specifically, deletion of theluxoperon, which abrogates symbiont luminescence—reduced the symbiosis-dependent transcriptome of the light organ by two-thirds. In addition, while the gills responded similarly to light-organ colonization by either the wild-type or mutant, luminescence was required for all of the colonization-associated transcriptional responses in the juvenile eye. This study defines not only the impact of symbiont colonization on the coordination of animal transcriptomes, but also provides insight into how such changes might impact the behavior and ecology of the host.

Candida albicanswhite and opaque cells exhibit distinct spectra of organ colonization in mouse models of infection

Candida albicans, a species of fungi, can thrive in diverse niches of its mammalian hosts; it is a normal resident of the GI tract and mucosal surfaces but it can also enter the bloodstream and colonize internal organs causing serious disease. The ability ofC. albicansto thrive in these different host environments has been attributed, at least in part, to its ability to assume different morphological forms. In this work, we examine one such morphological change known as white-opaque switching. White cells are the default state ofC. albicans, and most animal studies have been carried out exclusively with white cells. Here, we compared the proliferation of white and opaque cells in two murine models of infection and also monitored, using specially constructed strains, switching between the two states in the host. We found that white cells outcompeted opaque cells in many niches; however, we show for the first time that in some organs (specifically, the heart and spleen), opaque cells competed favorably with white cells and, when injected on their own, could colonize these organs. In environments where the introduced white cells outcompeted the introduced opaque cells, we observed high rates of opaque-to-white switching. We did not observe white-to-opaque switching in any of the niches we examined.