Context-dependent signalling

Signalling pathways modulate cellular responses in developmental and regenerative processes but can also be misused by cancer cells to promote tissue invasion and growth. How signalling outputs are integrated to direct a variety of responses ranging from organ repair to tumour onset remains elusive. Jorge Beira and collaborators at ETH Zürich (Switzerland) revealed that similar signals and pathways are differentially regulated during tissue regeneration on the one hand, and tumorigenesis on the other. Interestingly, signalling hierarchies active in Drosophila ph tumours are distinct from the role these same pathways have in protecting normal tissues undergoing stress or injury, thus promoting regeneration.

The paper entitled "Signalling crosstalk during early tumorigenesis in the absence of Polycomb silencing" was published in PLoS Genetics.

 

Zebrafish larvae xenografts for precision medicine

Despite advances in targeted cancer treatments, methods to predict how a specific cancer will respond to a given therapy are still lacking. Consequently, patients go through rounds of trial-and-error approaches based on guidelines to find the best treatment, often subjected to unnecessary toxicity. Using cell lines, Rita Fior and collaborators at the Champalimaud Centre for the Unknown, used zebrafish larvae xenografts as sensors for cancer behavior and therapy guideline screening. Their data show not only sufficient resolution to distinguish functional tumor behaviors in just 4 days but also differential sensitivity to colorectal cancer therapy. As proof-of-principle, they provide evidence for similar behavior response to therapies in patients as in zebrafish patient-derived xenografts. Altogether, their results suggest zebrafish larvae xenografts as a promising in vivo screening platform for precision medicine.

See the article entitled “Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts” published in PNAS. 

Notch decides numbers of motile versus nonmotile cilia in the LR Organizer

Foxj1a is necessary and sufficient to specify motile cilia. Using transcriptional studies and slow-scan two-photon live imaging capable of identifying the number of motile and immotile cilia, Bárbara Tavares and collaborators at CEDOC established that the final number of motile cilia depends on Notch signalling (NS). They found that despite all left-right organizer (LRO) cells express foxj1aand the ciliary axonemes of these cells have dynein arms, some cilia remain immotile. They found that this decision is taken early in development in the Kupffer’s Vesicle (KV) precursors the readout being her12 transcription. They further demonstrated that overexpression of either her12 or Notch intracellular domain (NICD) increases the number of immotile cilia at the expense of motile cilia, and leads to an accumulation of immotile cilia at the anterior half of the KV. This disrupts the normal fluid flow intensity and pattern, with consequent impact on left-right (L-R) axis establishment.

See the article entitled “Notch/Her12 signalling modulates, motile/immotile cilia ratio downstream of Foxj1a in zebrafish left-right organizer” published in eLIFE.

Mechanics and cancer

 

Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. In a collaborative project, the labs of Florence Janody (IGC) and Joana Paredes (i3S) demonstrated that cells from a human breast cell line with conditional Src induction undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. The team also found that EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, this work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. The authors propose that a careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies. The paper by Tavares et al. entitled “Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells” was published in Nature Communications.

 

 

Impaired fetal myogenesis marks MDC1A onset in mice

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a devastating neuromuscular disease in which patients demonstrate hypotonia from birth. MDC1A involves muscle wasting, inflammation and fibrosis, but how the disease starts is presently unknown.

The group of Sólveig Thorsteinsdóttir at FCUL collaborated with the team of Dean J. Burkin at the University of Nevada and used the dyW mouse model for MDC1A to study the effect of laminin α2-chain deficiency on skeletal muscle development in vivo. They found that during secondary myogenesis, dyW-/- muscles exhibit impaired growth, fail to maintain the normal number of Pax7-positive muscle stem cells and experience a dramatic drop in the number of Myogenin-positive myoblasts.

The paper by Andreia Nunes et al. entitled “Impaired fetal muscle development and JAK-STAT activation mark disease onset and progression in a mouse model for merosin-deficient congenital muscular dystrophy” shows for the first time that MDC1A starts before birth in dyW-/-  mice and that the onset of the disease in utero is marked by impaired fetal myogenesis.