Hh signaling from de novo organizers drive lgl neoplasia in Drosophila epithelium

Bajpai, A. K.; Sinha, Prawal

doi:10.1016/j.ydbio.2019.09.011

Cited by 7 publications

(12 citation statements)

References 48 publications

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“…The rescue and subsequent transformation of lgl clones with simultaneous perturbations in hsrω transcript levels was largely limited to the proximal wing, since the lgl clones generated in the distal wing continued to undergo apoptosis, as reflected in the elevated levels of Caspase in such clones (marked by arrow in Figure 4A-C). Such disparities in neoplastic propensities of lgl clones are consistent with earlier reports [10,44,45], and could be attributed to the underlying developmental programs [10] or to tissue intrinsic local cytoarchitecture [45].…”

Section: Hsrωmediated Tumor Cooperation Does Not Suffice To Override Developmentallyregulated Itssupporting

confidence: 90%

A Gene Encoding an Architectural RNA,hsrω, is a Host Genetic Modifier of Cancer Progression inDrosophila

Bajpai

Kundu

et al. 2021

Preprint

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Cells incurring oncogenic hits are often eliminated by cell death via built-in anti-cancer defense mechanisms, broadly termed as intrinsic tumor suppression (ITS). Identification of genetic modifiers of ITS-induced cell death would provide better understanding of inherent tumor-resistance and/or susceptibility. Using a Drosophila model of loss of a tumor suppressor-mediated epithelial tumorigenesis, here we show that perturbations in levels of stress-responsive nuclear long non-coding RNA (lncRNA) hsrω gene, promote epithelial tumorigenesis. Thus, while somatic clones with loss of a tumor suppressor, Lgl, are eliminated by JNK-induced cell death, lgl mutant somatic clones induced either in an hsrω loss-of-function heterozygous genetic background, or upon cell autonomous up- or down-regulation of hsrω in lgl somatic clones, override the JNK-mediated cell death and progress to full blown tumors. These tumors display deregulation of Hippo pathway as seen from a gain of downstream target of inhibition, Diap1, an inhibitor of cell death. We finally show that downregulation in sat III non-coding RNA, a functional analog of hsrω in humans, increases sensitivity of cancer cells to cytotoxic stress-induced cell death. lncRNA hsrω, therefore, constitutes a novel genetic modifier of ITS in Drosophila and of stress-induced cell death in human cancers.SummaryA long non-coding RNA, hsrω, is a novel regulator of JNK-mediated intrinsic tumor suppression in Drosophila.Highlightslgl clones induced in hsrω heterozygous loss-of-function genetic background escape intrinsic tumor suppression (ITS).Perturbation of hsrω in lgl mutant clones, too, leads to their escape from ITS.hsrω homeostasis required for JNK-dependent ITS.Human sat III, a functional analog of hsrω, confers stress-resistant to human cancer cells.

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Section: Hsrωmediated Tumor Cooperation Does Not Suffice To Override Developmentallyregulated Itssupporting

confidence: 90%

A Gene Encoding an Architectural RNA,hsrω, is a Host Genetic Modifier of Cancer Progression inDrosophila

Bajpai

Kundu

et al. 2021

Preprint

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Section: Introductionmentioning

confidence: 99%

“…Lgl null mutant flies showed a gradual loss of tissue architecture and extended larval life in which cell proliferation never ceases (Froldi et al, 2008). Furthermore, lgl mutants comprising deficiencies of diverse regions in the second chromosome show neoplastic outgrowths in the brain, hematopoietic system, and intestines (Bajpai & Sinha, 2020). Melatonin (N-acetyl-5-methoxytryptamine) is an indolic compound secreted in a circadian manner by the pineal gland of human and mammals at an elevated level during darkness.…”

Section: Introductionmentioning

confidence: 99%

Melatonin improves cognitive behavior, oxidative stress, and metabolism in tumor‐prone lethal giant larvae mutant of Drosophila melanogaster

Wong

Sankaran

Jayapalan

et al. 2021

Arch Insect Biochem Physiol

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Mutant lethal giant larvae (lgl) flies (Drosophila melanogaster) are known to develop epithelial tumors with invasive characteristics. The present study has been conducted to investigate the influence of melatonin (0.025 mM) on behavioral responses of lgl mutant flies as well as on biochemical indices (redox homeostasis, carbohydrate and lipid metabolism, transaminases, and minerals) in hemolymph, and head and intestinal tissues. Behavioral abnormalities were quantitatively observed in lgl flies but were found normalized among melatonin‐treated lgl flies. Significantly decreased levels of lipid peroxidation products and antioxidants involved in redox homeostasis were observed in hemolymph and tissues of lgl flies, but had restored close to normalcy in melatonin‐treated flies. Carbohydrates including glucose, trehalose, and glycogen were decreased and increased in the hemolymph and tissues of lgl and melatonin‐treated lgl flies, respectively. Key enzymes of carbohydrate metabolism showed a significant increment in their levels in lgl mutants but had restored close to wild‐type baseline levels in melatonin‐treated flies. Variables of lipid metabolism showed significantly inverse levels in hemolymph and tissues of lgl flies, while normalization of most of these variables was observed in melatonin‐treated mutants. Lipase, chitinase, transaminases, and alkaline phosphatase showed an increment in their activities and minerals exhibited decrement in lgl flies; reversal of changes was observed under melatonin treatment. The impairment of cognition, disturbance of redox homeostasis and metabolic reprogramming in lgl flies, and restoration of normalcy in all these cellular and behavioral processes indicate that melatonin could act as oncostatic and cytoprotective agents in Drosophila.

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“…We also demonstrate that changing selector gene expression within an overgrowing clone can create interactions at the clone margin that are reminiscent of compartment boundaries and result in the production of morphogens. A recent study showed that forced expression of En in lgl clones can elicit similar phenomena in anterior clones ( 52 ). In addition, yki CA clones are often extruded, consistent with previous observations that heterotypic interactions caused by overexpressing patterning genes also promotes extrusion ( 14 – 16 ).…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway coactivator Yorkie can reprogram cell fates and create compartment-boundary–like interactions at clone margins

2020

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During development, tissue-specific patterns of gene expression are established by transcription factors and then stably maintained via epigenetic mechanisms. Cancer cells often express genes that are inappropriate for that tissue or developmental stage. Here, we show that high activity levels of Yki, the Hippo pathway coactivator that causes overgrowth in Drosophila imaginal discs, can also disrupt cell fates by altering expression of selector genes like engrailed (en) and Ultrabithorax (Ubx). Posterior clones expressing activated Yki can down-regulate en and express an anterior selector gene, cubitus interruptus (ci). The microRNA bantam and the chromatin regulator Taranis both function downstream of Yki in promoting ci expression. The boundary between Yki-expressing posterior clones and surrounding wild-type cells acquires properties reminiscent of the anteroposterior compartment boundary; Hedgehog signaling pathway activation results in production of Dpp. Thus, at least in principle, heterotypic interactions between Yki-expressing cells and their neighbors could activate boundary-specific signaling mechanisms.

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Hh signaling from de novo organizers drive lgl neoplasia in Drosophila epithelium

Cited by 7 publications

References 48 publications

A Gene Encoding an Architectural RNA,hsrω, is a Host Genetic Modifier of Cancer Progression inDrosophila

A Gene Encoding an Architectural RNA,hsrω, is a Host Genetic Modifier of Cancer Progression inDrosophila

Melatonin improves cognitive behavior, oxidative stress, and metabolism in tumor‐prone lethal giant larvae mutant of Drosophila melanogaster

The Hippo pathway coactivator Yorkie can reprogram cell fates and create compartment-boundary–like interactions at clone margins

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