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. 

 

 

Differentiation by counteracting progenitor fate

The generation of neurons from neural stem cells requires large-scale changes in gene expression that are controlled to a large extent by proneural transcription factors, such as Ascl1. While recent studies have characterized the differentiation genes activated by proneural factors, less is known on the mechanisms that suppress progenitor cell identity. Diogo Castro’s group at the IGC showed that Ascl1 induces the transcription factor MyT1 while promoting neuronal differentiation. In the article Vasconcelos et al entitled “MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis” they combined functional studies of MyT1 during neurogenesis with the characterization of its transcriptional program. MyT1 binding is associated with repression of gene transcription in neural progenitor cells. It promotes neuronal differentiation by counteracting the inhibitory activity of Notch signaling at multiple levels, targeting the Notch1 receptor and many of its downstream targets. Thus, Ascl1 suppresses Notch signaling cell-autonomously via MyT1, coupling neuronal differentiation with repression of the progenitor fate.

 

Notch and Hedgehog in specifying organ primordium

The avian thymus and parathyroid (T/PT) common primordium derives from the endoderm of the third and fourth pharyngeal pouches(3/4PP). The molecular mechanisms that govern T/PT development are not fully understood. Hélia Neves’ group at IMM/FMUL studied the effects of Notch and Hedgehog signaling modulation during common primordium development using in vitro, in vivo and in ovo approaches. Their results, published in an article by Figueiredo et al entitled “Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation”, show that impairment of Notch activity reduced thymus- and parathyroid-fated domains in the 3/4PP and compromised the development of the parathyroid glands and showed that it acts in a Hedgehog-dependent manner. 

 

Of mice and ... snakes

Vertebrates exhibit a remarkable variation in trunk and tail lengths. However, how this diversity comes about is mostly unknown. Rita Aires et al. report in Developmental Cell that Oct4 is a key regulator of vertebrate trunk length diversity. They show that snake embryos express Oct4 for longer periods than mouse embryos and provide evidence to suggest that differential genomic rearrangements of noncoding regions near the Oct4 locus may underlie this phenomenon in snakes. Also see Latest News in Science.