During tumor growth—when nutrient and anabolic demands are high—autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras‐driven tumors ...additionally invoke non‐autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well‐characterized malignant tumor model in Drosophila melanogaster. Micro‐computed X‐ray tomography and metabolic profiling reveal that RasV12; scrib−/− tumors grow 10‐fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, ‐motility, ‐feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.
Synopsis
Autophagy maintains mitochondrial health and nutrient recycling in tumor cells, and promotes the transfer of amino acids from microenvironmental to tumor cells, thereby sustaining tumor metabolism and growth. In this study, X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster.
RasV12, scrib−/− tumors induce organ wasting and cause release of amino acids and sugar into circulation.
Systemic autophagy mediates muscle wasting and nutrient release.
Tumor biomass increasingly derive from host tissues as wasting ensues.
X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster.
The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as ...Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic RasV12 and the loss of the tumor suppressor scribble in flies, this and other tumor models have provided new concepts and findings in cancer biology that has remarkable parallels and relevance to human cancer. Here we review findings using the RasV12; scrib−/− tumor model and how it has contributed to our understanding of how these initial simple genetic insults cooperate within the tumor cell to set in motion the malignant transformation program leading to tumor growth through cell growth, cell survival and proliferation, dismantling of cell–cell interactions, degradation of basement membrane and spreading to other organs. Recent findings have demonstrated that cooperativity goes beyond cell intrinsic mechanisms as the tumor interacts with the immediate cells of the microenvironment, the immune system and systemic organs to eventually facilitate malignant progression.
Cell competition eradicates weaker cells from an epithelium and is important for organ homeostasis. In this issue of Developmental Cell, Nagata et al. (2019) uncover that eradication of loser cells ...depends on autophagy-mediated cell death.
Cell competition eradicates weaker cells from an epithelium and is important for organ homeostasis. In this issue of Developmental Cell, Nagata et al. (2019) uncover that eradication of loser cells depends on autophagy-mediated cell death.
Pediatric neural tumors are often initiated during early development and can undergo very rapid transformation. However, the molecular basis of this early malignant susceptibility remains unknown. ...During Drosophila development, neural stem cells (NSCs) divide asymmetrically and generate intermediate progenitors that rapidly differentiate in neurons. Upon gene inactivation, these progeny can dedifferentiate and generate malignant tumors. Here, we find that intermediate progenitors are prone to malignancy only when born during an early window of development while expressing the transcription factor Chinmo, and the mRNA-binding proteins Imp/IGF2BP and Lin-28. These genes compose an oncogenic module that is coopted upon dedifferentiation of early-born intermediate progenitors to drive unlimited tumor growth. In late larvae, temporal transcription factor progression in NSCs silences the module, thereby limiting mitotic potential and terminating the window of malignant susceptibility. Thus, this study identifies the gene regulatory network that confers malignant potential to neural tumors with early developmental origins.
Whether common principles regulate the self-renewing potential of neural stem cells (NSCs) throughout the developing central nervous system is still unclear. In the
ventral nerve cord and central ...brain, asymmetrically dividing NSCs, called neuroblasts (NBs), progress through a series of sequentially expressed transcription factors that limits self-renewal by silencing a genetic module involving the transcription factor Chinmo. Here, we find that Chinmo also promotes neuroepithelium growth in the optic lobe during early larval stages by boosting symmetric self-renewing divisions while preventing differentiation. Neuroepithelium differentiation in late larvae requires the transcriptional silencing of
by ecdysone, the main steroid hormone, therefore allowing coordination of neural stem cell self-renewal with organismal growth. In contrast,
silencing in NBs is post-transcriptional and does not require ecdysone. Thus, during
development, humoral cues or tissue-intrinsic temporal specification programs respectively limit self-renewal in different types of neural progenitors through the transcriptional and post-transcriptional regulation of the same transcription factor.
La mise en place du système nerveux central (SNC) repose sur l’équilibre entre prolifération et différenciation des cellules souches neurales. Chez les mammifères, le SNC suit un développement ...biphasique avec une phase proliférative pendant laquelle les cellules souches neuroépithéliales s’amplifient par division symétrique puis une phase neurogénique pendant laquelle elles sont converties en progéniteurs neuraux se divisant de manière asymétrique pour générer leurs neurones. De nombreux mécanismes sont impliqués dans la régulation des phases du développement du SNC, mais leur coordination au cours du développement demeure mal comprise. Dans ce contexte, la famille des gènes oncofoetaux s’avère très pertinente. Ces gènes sont exprimés au cours du développement précoce où ils coordonnent la synchronie des évènements développementaux. Ils sont éteints en fin de développement mais leur réexpression dans de nombreux cancers témoigne de leur caractère oncogénique. Les mécanismes contrôlant leur extinction au cours du développement ou leur réactivation lors de la tumorigenèse restent obscurs. Durant ma thèse de doctorat, j’ai utilisé la mouche drosophile pour mieux comprendre comment des gènes aux propriétés oncofoetales sont contrôlés et coordonnent les évènements développementaux du SNC. Mon projet de thèse a permis d’identifier le gène aux propriétés oncofoetales, Chinmo, comme impliqué dans le développement du lobe optique de la drosophile pendant sa phase proliférative et dans le processus cancéreux. Ainsi, ces travaux pourront contribuer à une meilleure compréhension du rôle des gènes oncofoetaux dans le contexte développemental et tumoral chez les mammifères.
The development of the central nervous system (CNS) relies on the tight balance between proliferation and differentiation of the neural stem cells. The mammal CNS develops in two phases: the proliferative phase during which the neuroepithelial stem cells amplify through symmetric divisions and a neurogenic phase during which they are converted into neural progenitors that divide asymmetrically to generate their neuronal progeny. Several mechanisms are involved in the regulation of both phases of the CNS development however their coordination in the course of the development remains unclear. In this context, the oncofetal gene family seems particularly relevant. These genes are expressed during the early development where they coordinate the synchrony of the developmental events. They are switched off during the late development but their reexpression in numerous cancers brings evidence of their oncegenicity. The mechanisms governing their repression along the development and their reactivation in cancers are not well understood. During my thesis, I used the Drosophila model to better understand how oncofetal genes are controlled and regulate the developmental events in the CNS. My thesis project allowed to identify an oncofetal-like gene, Chinmo, involved in the development of the Drosophila CNS during its proliferative and in the cancerization process. This work may contribute to a better understanding of the role of oncofetal genes both in the developmental and the tumoral context in mammals.
Abstract
During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors ...additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. Thus, host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.
Citation Format: Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M. Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M. Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten. Host autophagy mediates organ wasting and nutrient mobilization for tumor growth abstract. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA14.
Abstract
A 2-yr study was conducted at Black Belt Research and Extension Center in Marion Junction, AL, to evaluate the effect of nitrogen (N) fertilizer application rate on forage production ...characteristics, nutritive value, and animal performance of beef heifers grazing a mixture of native warm-season grasses (NWSG) including big bluestem, little bluestem, and indiangrass. Six, two-hectare plots were randomly assigned to one of two treatments (0 or 67 kg N ha-1 applied in early April; n = 3 replications per treatment). Paddocks were continuously stocked with four weaned Angus × Simmental beef heifers (initial BW 288 ± 7 kg) from late May/early June through mid-to-late August during 2018 (73 grazing d) and 2019 (70 grazing d), respectively. Put-and-take cattle were used to manage forage to a target of 38 cm. Forage mass and canopy heights were collected every two weeks during the trial. Visual ground cover ratings, canopy light interception, and botanical composition were measured at the beginning and end of the trial in each year. Hand-plucked samples were collected every two weeks during the grazing trial to determine forage nutritional value. Data were analyzed using the PROC MIXED procedure in SAS 9.4, and differences were declared significant when P ≤ 0.05. Nitrogen fertilized NWSG had greater crude protein (P < 0.0001), sward heights (P = 0.0003), and canopy light interception at the beginning of the season (P = 0.0049) compared to non-fertilized paddocks. However, there were no differences (P ≥ 0.05) among N-fertility treatments for mean forage mass, heifer ADG, or BCS across the 2-yr study. Botanical composition data indicated that indiangrass decreased from 64% to 61% (P = 0.0022) and weed pressure increased from 11% to 15% (P = 0.0064) across the summer grazing season. Canopy light interception decreased by 51% from early June to August in fertilized NWSG and 26% in unfertilized paddocks, respectively. These data illustrate that NWSG systems may provide a viable grazing system in the summer months under reduced N inputs.
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