Systemic muscle wasting and coordinated tumour response drive tumourigenesis

Newton, Holly; Wang, Yi Fang; Camplese, Laura; Mokochinski, João Benhur; Kramer, Holger; Brown, André Ex; Fets, Louise; Hirabayashi, Susumu

doi:10.1038/s41467-020-18502-9

Cited by 42 publications

(40 citation statements)

References 46 publications

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“…For example, aberrant activation of yki 3SA , a homolog of the human oncogene YAP1 , in intestinal stem cells (ISCs) results in severe tumor cell overproliferation in the gut and subsequent muscle dysfunction, lipid loss, and hyperglycemia ( Kwon et al, 2015 ). Similar host wasting effects were also reported in other fly tumor models ( Figueroa-Clarevega and Bilder, 2015 ; Katheder et al, 2017 ; Newton et al, 2020 ; Nie et al, 2019 ). As there is no evidence of metastasis from yki 3SA -gut tumors, a likely explanation is that host wasting is caused by tumor-secreted proteins that act remotely on host tissues.…”

Section: Introductionsupporting

confidence: 86%

Coordination of tumor growth and host wasting by tumor-derived Upd3

Ding

Xiang

et al. 2021

Cell Reports

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SUMMARY yki -induced gut tumors in Drosophila are associated with host wasting, including muscle dysfunction, lipid loss, and hyperglycemia, a condition reminiscent of human cancer cachexia. We previously used this model to identify tumor-derived ligands that contribute to host wasting. To identify additional molecular networks involved in host-tumor interactions, we develop PathON, a web-based tool analyzing the major signaling pathways in Drosophila , and uncover the Upd3/Jak/Stat axis as an important modulator. We find that yki -gut tumors secrete Upd3 to promote self-overproliferation and enhance Jak/Stat signaling in host organs to cause wasting, including muscle dysfunction, lipid loss, and hyperglycemia. We further reveal that Upd3/Jak/Stat signaling in the host organs directly triggers the expression of ImpL2 , an antagonistic binding protein for insulin-like peptides, to impair insulin signaling and energy balance. Altogether, our results demonstrate that yki -gut tumors produce a Jak/Stat pathway ligand, Upd3, that regulates both self-growth and host wasting.

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Section: Introductionsupporting

confidence: 86%

Coordination of tumor growth and host wasting by tumor-derived Upd3

Ding

Xiang

et al. 2021

Cell Reports

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“…3 D). The molecular underpinnings of the effect sugar has on Ras V12 csk −/− tumor progression have been elucidated in several studies ( Hirabayashi et al, 2013 ; Hirabayashi and Cagan, 2015 ; Newton et al, 2020 ). Briefly, the Ras V12 csk −/− genotype synergizes with high-sugar feeding to activate salt-inducible kinases (SIKs) that function downstream of InR signaling ( Choi et al, 2015 ).…”

Section: Links Between Diet and Cancermentioning

confidence: 99%

“…This forms an InR-SIK-Yki-Wg/InR signaling loop that potentiates glucose uptake, insulin sensitivity and secondary tumor formation. Moreover, via the canonical intracellular aa sensor InR-target of rapamycin (TOR) axis, this loop is linked to another positive feedback involving production and secretion of the fibroblast growth factor ligand Branchless (Bnl) to sustain muscle wasting ( Newton et al, 2020 ). Muscle wasting supplies the tumors with proline that, in turn, strengthens TOR activation and drives tumor growth.…”

Section: Links Between Diet and Cancermentioning

confidence: 99%

Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Wong

Verheyen

2021

Disease Models &Amp; Mechanisms

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Cancer cells constantly reprogram their metabolism as the disease progresses. However, our understanding of the metabolic complexity of cancer remains incomplete. Extensive research in the fruit fly Drosophila has established numerous tumor models ranging from hyperplasia to neoplasia. These fly tumor models exhibit a broad range of metabolic profiles and varying nutrient sensitivity. Genetic studies show that fly tumors can use various alternative strategies, such as feedback circuits and nutrient-sensing machinery, to acquire and consolidate distinct metabolic profiles. These studies not only provide fresh insights into the causes and functional relevance of metabolic reprogramming but also identify metabolic vulnerabilities as potential targets for cancer therapy. Here, we review the conceptual advances in cancer metabolism derived from comparing and contrasting the metabolic profiles of fly tumor models, with a particular focus on the Warburg effect, mitochondrial metabolism, and the links between diet and cancer.

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“…We find that early tumor growth sources a majority of biomass carbon from the food, but that carbons are increasingly incorporated from the host tissues as tumor growth progresses (Fig 5f, g , but that the fat body volume is retained with increased signs of steatosis. Muscle wasting was also reported to be induced by fibroblast growth factor secretion in a Ras V12 , Csk-IR larval model while this paper was being revised 17 ctrl (n=45), Ras V12 ; scrib -/-(n=30), Ras V12 , scrib -/-, atg13 -/-//atg13 -/-(n=30) and ey3.5-atg13; Ras V12 , scrib -/-, atg13 -/-//atg13 -/-(n=29) and at day 10 Ras V12 ; scrib -/-(n=40), Ras V12 , scrib -/-, atg13 -/-//atg13 -/-(n=25) and ey3.5-atg13; Ras V12 , scrib -/-, atg13 -/-//atg13 -/-(n=28). (g) Quantification of tumor volumes day 6 Ras V12 ; ctrl (n=7), Ras V12 ; scrib -/-(n=11) and day 8 Ras V12 ; scrib -/-(n=13), Ras V12 , scrib -/-, atg13 -/-//atg13 -/-(n=9) and ey3.5-atg13; Ras V12 , scrib -/-, atg13 -/-//atg13 -/-(n=9).…”

Section: Host-derived Nutrients Constitute the Main Source Of Tumor Bmentioning

confidence: 99%

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

Khezri

Holland

Schoborg

et al. 2020

Preprint

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During tumor growth - when nutrient and anabolic demands are high – autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling1. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids2–4. 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.

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Systemic muscle wasting and coordinated tumour response drive tumourigenesis

Cited by 42 publications

References 46 publications

Coordination of tumor growth and host wasting by tumor-derived Upd3

Coordination of tumor growth and host wasting by tumor-derived Upd3

Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

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