Biology subjects

Teles-Reis, J.

Publications and source records attributed to Teles-Reis, J..

4 recordsLinked to original sources

bioRxiv2026

Interclonal cooperation and suppression shape early Ras-driven tumour growth

Cancer is generally thought to be caused by expansion of a single mutant cell. However, analyses of human early lesions show that tumours can originate from several genetically distinct cell populations1-5. How neighbouring mutant clones interact to shape tumourigenesis, and which driver genes mediate these effects is largely unexplored. Here, we use an in vivo mosaic Drosophila epithelial model to systematically test interclonal interactions during early Ras-driven tumourigenesis. We screened 88 recurrent RAS co-mutated driver genes in human carcinomas for their ability to modify Ras-clone growth when disrupted in neighbouring epithelial clones. This uncovered two opposing classes of interactions: Interclonal cooperativity, where neighbouring mutant clones promote the overgrowth of Ras mutant tumours, and interclonal suppression, in which neighbours restrain Ras tumours, unexpectedly improving host survival. The strongest suppressive modifiers included canonical cell competition regulators, including Myc, archipelago (ago/FBXW7), and taiman (tai/NCOA1-3). In contrast, the strongest cooperative modifiers were disruptions of XNP/ATRX and SWI/SNF chromatin remodelling subunits (including Osa/ARID1A, Bap170/ARID2, Polybromo/PBRM1, among others), which in neighbouring cells induce a wound-like inflammatory program and drive an anabolic, pro-growth state in Ras tumours. Notably, the disruption of SWI/SNF components cell autonomously within Ras tumours confers no cooperativity. We show that interclonal cooperative Ras tumour growth requires reactive oxidative species and prostaglandin synthesis in SWI/SNF-disrupted clones. Together, this study provides a catalogue and emerging principles of cooperative and suppressive interclonal interactions among recurrent RAS co-mutated drivers, extending the rules of oncogenic cooperation beyond cell intrinsic co-mutation.

cancer biology↗

bioRxiv2024

EyaHOST a modular genetic system for investigation of intercellular and tumor-host interactions in Drosophila melanogaster

Cell biology and genetic analysis of intracellular, intercellular and inter-organ interaction studies in animal models are key for understanding development, physiology, and disease. The MARCM technique can emulate tumor development by simultaneous clonal tumor suppressor loss-of-function generation coupled with GAL4-UAS-driven oncogene and marker expression, but the utility is limited for studying tumor-host interactions due to genetic constraints. To overcome this, we introduce EyaHOST, a novel system that replaces MARCM with the QF2-QUAS binary gene expression system under the eya promoter control, unleashing the fly community genome-wide GAL4-UAS driven tools to manipulate any host cells or tissue at scale. EyaHOST generates epithelial clones in the eye epithelium similar to MARCM. EyaHOST-driven RasV12 oncogene overexpression coupled with scribble tumor suppressor knockdown recapitulates key cancer features, including systemic catabolic switching and organ wasting. We demonstrate effective tissue-specific manipulation of host compartments such as neighbouring epithelial cells, immune cells, fat body, and muscle using fly avatars with tissue-specific GAL4 drivers. Organ-specific inhibition of autophagy or stimulation of growth-signaling through PTEN knockdown in fat body or muscle prevents cachexia-like wasting. Additionally, we show that RasV12, scribRNAi tumors induce caspase-driven apoptosis in the epithelial microenvironment. Inhibition of apoptosis by p35 expression in the microenvironment promotes tumor growth. EyaHOST offers a versatile modular platform for dissecting tumor-host interactions and other mechanisms involving intercellular and inter-organ communication in Drosophila. Highlights*eyes absent, eye disc-specific enhancer drives clonal KD recombinase flip-out activated QF2 expression in the larval eye epithelium for simultaneous QUAS-driven gain and loss-of-function analysis of gene function. *Clones are visualized by QUAS-tagBFP or QUAS-eGFP facilitating analysis of existing fluorescent reporters. *The GAL4-UAS system and existing genome-wide genetic tools are released to independently manipulate any cell population in the animal for cell biology, intercellular or inter-organ analysis for developmental, physiological, or disease model analysis. *Fly avatars for tumor-host interaction studies with multiple organs allow live monitoring and manipulation of tumors and organs in translucent larva.

cancer biology↗

bioRxiv2024

Oncogenic Ras-driven Dorsal/NF-κB signaling contributes to tumorigenesis in a Drosophila carcinoma model

Cancer-driving mutations synergize with inflammatory stress signaling pathways during carcinogenesis. Drosophila melanogaster tumour models are increasingly recognized as models to inform conserved molecular mechanisms of tumorigenesis with both local and systemic effects of cancer. Although initial discoveries of the Toll-NF{kappa}B signaling pathway in development and immunity was pioneered in Drosophila, limited information is available for its role in cancer progression. Using a well-studied cooperative RasV12 -driven epithelial-derived tumour model, we here describe functions of Toll-NF-{kappa}B signaling in malignant RasV12, scrib- tumors. The extracellular Toll pathway components ModSP and PGRP-SA and intracellular signaling Kinase, Pelle/IRAK, are rate-limiting for tumor growth. The Toll pathway NF{kappa}B protein Dorsal, as well as cactus/I{kappa}B show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic RasV12, and not loss of scribble, confers increased expression and heterogenous distribution of two Dorsal isoforms, DorsalA and DorsalB in different tumour cell populations. Mechanistic analyses demonstrates that Dorsal drives growth and malignancy by suppressing differentiation, counteracting apoptosis and promoting invasion of RasV12, scrib- tumors genetically dependent on twist and snail.

cancer biology↗

bioRxiv2021

Fate transitions in Drosophila neural lineages: a single cell road map to mature neurons.

Neuron specification and maturation are essential for proper central nervous system development. However, the precise mechanisms that govern neuronal maturation remain poorly understood. Here, we use single-cell RNA sequencing, combined with a conditional genetic strategy to analyse neuronal lineages and their new born neurons in the Drosophila larval brain. A focused analysis on the transcriptional alterations that occur right after neuron generation revealed that neuron maturation starts shortly after neuronal birth, with transcription, but no translation, of mature neuronal features such as neurotransmitter (NT) genes. Using NT gene Choline acetyltransferase as an example, we show that the timings of translation initiation are not solely dependent on neuron age but are rather coordinated with the animal developmental stage. This study is the first characterization of the initial phases of neuron maturation, supporting a model where neuron maturation is coordinated with the animal developmental stage through post-transcriptional regulation of terminal effector genes.

neuroscience↗