Cell-cell interactions that drive tumorigenesis in <i>Drosophila</i>

Enomoto, Mika; Igaki, Tatsushi

doi:10.1080/19336934.2022.2148828

Cited by 5 publications

(2 citation statements)

References 114 publications

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“…Tissue repair and tumor development share striking similarities; in fact, tumors have long been compared to non-healing wounds (Dvorak, 1986). Accordingly, Drosophila tumor models activate JNK/AP1 and JAK/STAT signaling, which promotes tumor progression (Enomoto & Igaki, 2022;Herrera & Bach, 2019;La Marca & Richardson, 2020). To support their growth, tumors secrete signaling molecules that initiate inter-organ signaling and systemic metabolic responses (Bilder et al, 2021;Hodgson et al, 2021;Liu et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

PDK-1/S6K and mTORC1 bypass systemic growth restrictions to promote regeneration

Maya,

Nogay,

Heckmann

et al. 2024

Preprint

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Tissue damage and inflammation trigger systemic signals that induce catabolic breakdown and nutrient release in distant organs, a process well-characterized in the context of tumor cachexia. While mechanisms allowing tumors to circumvent these systemic growth restrictions are known, the physiological processes that overcome inflammation-induced growth restrictions to support tissue repair and regeneration remain largely unexplored. In our study, we use a model of tissue inflammation and regeneration in developingDrosophilaimaginal discs to dissect the key metabolic and signaling adaptations that help tissue overcome systemic growth restrictions. Our findings reveal a unique metabolic strategy used by rapidly proliferating cells in the regenerating domain. Instead of relying on the conventional Insulin-PI3K-Akt signaling pathway, these cells utilize a JAK/STAT-PDK1-S6K axis. This adaptation facilitates sustained protein synthesis and cellular growth despite the systemic catabolism associated with low insulin signaling. Specifically, we find that catabolic breakdown of the fat body is driven by the insulin-binding factor Impl2, which is expressed at the site of inflammatory damage. Notably, regenerative proliferation is also supported by mTORC1 activity and is associated with the upregulation of amino acid transporters in proliferating cells of the regenerating domain. These amino acid transporters align with a specific amino acid metabolite signature in the hemolymph, revealing a specialized metabolic program that meets the demands of fast-proliferating cells. Our work provides insight into how regenerating tissues rewire signaling pathways and adapt their metabolic growth to coordinate tissue repair with a conserved systemic nutrient provision response. These findings have important implications for understanding human diseases such as chronic wounds and cancer.

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Section: Introductionmentioning

confidence: 99%

PDK-1/S6K and mTORC1 bypass systemic growth restrictions to promote regeneration

Maya,

Nogay,

Heckmann

et al. 2024

Preprint

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“…The powerful genetic tools available in Drosophila make it an optimal model system for elucidating the mechanisms of oncogenic intercellular communications (13)(14)(15)(16)(17). Accumulating evidence suggests that Drosophila genetic models faithfully replicate in vivo oncogenic cell-cell interactions, as clones harboring distinct oncogenic mutations can collaboratively promote tumor progression (18,19). For example, oncogenic Ras (Ras V12 ) clones with defects in the mitochondrial respiratory complex could lead to the malignancy of neighboring benign Ras V12 tumors through the induction of Unpaired (Upd, an IL-6 homolog) and Wingless (Wg, a Wnt homolog) (20).…”

Section: Introductionmentioning

confidence: 99%

Macrophages facilitate interclonal cooperation-induced tumor heterogeneity and malignancy by activating the innate immune signaling

Zhao,

Guo,

Kuang

et al. 2024

Preprint

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Tumor heterogeneity is a common hallmark of cancer and is considered a major cause of treatment failure and relapse, yet it remains poorly understood how various types of cells communicate within the tumor microenvironment (TME) to regulate tumor progressionin vivo. Here we establish a tumor heterogeneity model inDrosophilaeye epithelium by mutating the tricellular junction proteinM6in cells surroundingRasV12benign tumors and dissect thein vivomechanisms underlying interclonal cooperation-induced malignancy by utilizing sophisticated genetic techniques in conjunction with single-cell RNA sequencing (scRNA-seq). Our findings reveal that loss ofM6facilitates the malignant transformation of neighboringRasV12tumors by activating the Toll signaling, the innate immune response pathway. Notably, inhibiting Toll signaling impedes tumor progression, whereas its activation synergistically promotesRasV12tumor malignancy by inactivating the Hippo pathway. Mechanistically,RasV12tumors surrounded byM6mutant clones lead to increased recruitment of hemocytes, which are the equivalent of macrophages inDrosophila, in a JNK pathway-dependent manner. Consequently, these tumor-associated macrophages secrete the Spatzle (Spz) ligand, which subsequently activates the Toll receptor within theRasV12tumors, thereby triggering tumorigenesis. In summary, our study elucidates the complexin vivointeractions between genetically distinct oncogenic cells and between tumors and macrophages, shedding light on how macrophages exploit the innate immune signaling within tumors to regulate tumor heterogeneity and promote tumor progression.Significance statementIntratumoral heterogeneity profoundly affects cancer development and treatment in human tumors. The intricate nature of tumor cells and the presence of diverse cell types pose challenges to uncoveringin vivomechanisms responsible for heterogeneity. OurDrosophilatumor heterogeneity model reveals that fruit fly macrophages promotes both tumor heterogeneity and malignancy. Following recruitment by tumor cells, these macrophages secrete the ligand Spz to activate the Toll signaling pathway within tumor cells, which subsequently inactivates the Hippo pathway to drive tumorigenesis. Our study highlights the crucial role of hemocytes as intermediaries in coordinating tumor heterogeneity and facilitating intercellular communication between different cells within the TME.

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On a new mechanism of the emergence of spatial distributions in biological models

Kazmierczak,

Volpert

2025

Applied Mathematics Letters

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Cell-cell interactions that drive tumorigenesis in Drosophila

Cited by 5 publications

References 114 publications

PDK-1/S6K and mTORC1 bypass systemic growth restrictions to promote regeneration

PDK-1/S6K and mTORC1 bypass systemic growth restrictions to promote regeneration

Macrophages facilitate interclonal cooperation-induced tumor heterogeneity and malignancy by activating the innate immune signaling

On a new mechanism of the emergence of spatial distributions in biological models

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