Unscheduled expression of embryonic genes can lead to tumor formation
Tumor initiation is often linked to a loss of cellular identity. While key instructive genes are crucial during embryogenesis, many of these are then silenced during later developmental stages and in adulthood. Polycomb group proteins are among the main epigenetic silencing complexes and ensure appropriate silencing of many developmental genes in many cell types. In this work, Joana Torres, Jorge Beira and other collaborators at ETHZürich and Univ. Basel (Switzerland)investigated the gene signature of tumors caused by disruption of the Drosophila epigenetic regulator, polyhomeotic (ph). In larval tissue ph mutant cells show a shift towards an embryonic-like signature. Using loss- and gain-of-function experiments we uncovered the embryonic transcription factor knirps (kni) as a new oncogene. The oncogenic potential of kni lies in its ability to activate JAK/STAT signaling and block differentiation. Conversely, tumor growth in ph mutant cells can be substantially reduced by overexpressing a differentiation factor. This demonstrates that epigenetically derailed tumor conditions can be reversed when targeting key players in the transcriptional network. Overall, it also shows the importance of maintaining the OFF state for many embryonic genes after their function has been fulfilled. Read more about how genes that have key functions in the embryo can start to drive tumor formation at later stages, if they are not correctly turned off, in the published eLIFE paper entitled "A switch in transcription and cell fate governs the onset of an epigenetically-deregulated tumor in Drosophila".
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.