Dedifferentiation-derived neural stem cells exhibit perturbed temporal progression.

Dedifferentiation is the reversion of mature cells to a stem cell-like fate, whereby gene expression programs are altered and genes associated with multipotency are (re)expressed. Misexpression of multipotency factors and pathways causes the formation of ectopic neural stem cells (NSCs). Whether dedifferentiated NSCs faithfully produce the correct number and types of progeny, or undergo timely terminal differentiation, has not been assessed.

Tumor-derived MMPs regulate cachexia in a Drosophila cancer model.

Cachexia, the wasting syndrome commonly observed in advanced cancer patients, accounts for up to one-third of cancer-related mortalities. We have established a Drosophila larval model of organ wasting whereby epithelial overgrowth in eye-antennal discs leads to wasting of the adipose tissue and muscles. The wasting is associated with fat-body remodeling and muscle detachment and is dependent on tumor-secreted matrix metalloproteinase 1 (Mmp1).

Glial Hedgehog signalling and lipid metabolism regulate neural stem cell proliferation in Drosophila.

The final size and function of the adult central nervous system (CNS) are determined by neuronal lineages generated by neural stem cells (NSCs) in the developing brain. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-autonomous glial regulation of NB proliferation.

Interorgan communication in development and cancer.

Studies in model organisms have demonstrated that extensive communication occurs between distant organs both during development and in diseases such as cancer. Organs communicate with each other to coordinate growth and reach the correct size, while the fate of tumor cells depend on the outcome of their interaction with the immune system and peripheral tissues. In this review, we outline recent studies in Drosophila, which have enabled an improved understanding of the complex crosstalk between organs in the context of both organismal and tumor growth.

Histidine is selectively required for the growth of Myc-dependent dedifferentiation tumours in the CNS.

Rewired metabolism of glutamine in cancer has been well documented, but less is known about other amino acids such as histidine. Here, we use cancer models to show that decreasing the concentration of histidine in the diet strongly inhibits the growth of mutant clones induced by loss of Nerfin-1 or gain of Notch activity. In contrast, changes in dietary histidine have much less effect on the growth of wildtype neural stem cells and neural tumours.

The Scalloped and Nerfin-1 Transcription Factors Cooperate to Maintain Neuronal Cell Fate.

The ability of cells to stably maintain their fate is governed by specific transcription regulators. Here, we show that the Scalloped (Sd) and Nervous fingers-1 (Nerfin-1) transcription factors physically and functionally interact to maintain medulla neuron fate in the Drosophila melanogaster CNS. Using Targeted DamID, we find that Sd and Nerfin-1 occupy a highly overlapping set of target genes, including regulators of neural stem cell and neuron fate, and signaling pathways that regulate CNS development such as Notch and Hippo.

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua.

The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein.

Understanding how differentiation is maintained: lessons from the Drosophila brain.

The ability to maintain cells in a differentiated state and to prevent them from reprogramming into a multipotent state has recently emerged as a central theme in neural development as well as in oncogenesis. In the developing central nervous system (CNS) of the fruit fly Drosophila, several transcription factors were recently identified to be required in postmitotic cells to maintain differentiation, and in their absence, mature neurons undergo dedifferentiation, giving rise to proliferative neural stem cells and ultimately to tumor growth. In this review, we will highlight the current understanding of dedifferentiation and cell plasticity in the Drosophila CNS.

Multiple strategies of oxygen supply in Drosophila malignancies identify tracheogenesis as a novel cancer hallmark.

Angiogenesis is the term used to describe all the alterations in blood vessel growth induced by a tumour mass following hypoxic stress. The occurrence of multiple strategies of vessel recruitment favours drug resistance, greatly complicating the treatment of certain tumours. In Drosophila, oxygen is conveyed to the internal organs by the tracheal system, a closed tubular network whose role in cancer growth is so far unexplored.

The transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells.

Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation.

Connecting epithelial polarity, proliferation and cancer in Drosophila: the many faces of lgl loss of function.

Loss of cell polarity is a prominent feature of epithelial cancers. Several tumour-suppressor genes are indeed involved in establishing and maintaining a correct apical-basal polarity suggesting that a link exists between disruption of epithelial polarity and the control of cell proliferation. Nevertheless, the molecular basis of this link is only beginning to be unveiled.

dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells.

Genetic analyses in Drosophila epithelia have suggested that the phenomenon of "cell competition" could participate in organ homeostasis. It has been speculated that competition between different cell populations within a growing organ might play a role as either tumor promoter or tumor suppressor, depending on the cellular context. The evolutionarily conserved Hippo (Hpo) signaling pathway regulates organ size and prevents hyperplastic disease from flies to humans by restricting the activity of the transcriptional cofactor Yorkie (yki).

The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy.

Background: Neoplastic overgrowth depends on the cooperation of several mutations ultimately leading to major rearrangements in cellular behaviour. Precancerous cells are often removed by cell death from normal tissues in the early steps of the tumourigenic process, but the molecules responsible for such a fundamental safeguard process remain in part elusive. With the aim to investigate the molecular crosstalk occurring between precancerous and normal cells in vivo, we took advantage of the clonal analysis methods that are available in Drosophila for studying the phenotypes due to lethal giant larvae (lgl) neoplastic mutation induced in different backgrounds and tissues.