Flamingo, a Planar Cell Polarity Protein, is Required for Cell Competition in Drosophila Tumors and Development

Core Concepts

The planar cell polarity (PCP) protein Flamingo (Fmi) is required in winner cells to maintain their status and outcompete neighboring cells during both malignant tumor growth and developmental cell competition in Drosophila.

Abstract

The content explores the role of the planar cell polarity (PCP) protein Flamingo (Fmi) in cell competition, a process where cells of higher fitness ("winners") eliminate less fit neighbors ("losers"). Key highlights: In Drosophila, Fmi is required by winner cells to maintain their status and outcompete neighboring cells in multiple models of cell competition, including malignant tumors and developmental super-competition. The requirement for Fmi in winners is independent of its role in PCP signaling. Removing Fmi from the losers does not affect the competition outcome. Fmi's function in cell competition is also independent of its cadherin domains, suggesting it acts through a distinct mechanism, potentially related to its role as an adhesion G protein-coupled receptor (GPCR). Loss of Fmi in winner cells reduces their proliferation and increases apoptosis, impairing their ability to outcompete neighbors. The human orthologs of Fmi, CELSR1 and CELSR3, have been linked to poor prognosis in various cancers, suggesting a conserved role in promoting tumor aggressiveness through cell competition.

Stats

Drosophila RasV12, scrib RNAi tumors trigger apoptosis in the neighboring wildtype cells, as detected by Dcp1 staining. Removing Fmi from RasV12, scrib RNAi tumors results in excess apoptosis in the tumor cells compared to the surrounding wildtype tissue. Myc overexpressing (>>Myc) clones are on average 1.7 times larger than their wildtype twin spots, indicating they outcompete wildtype cells. When >>Myc clones lack Fmi, they become losers, being on average half as large as their wildtype twin spots.

Quotes

"Cells harboring mutations in proto-oncogenes or tumor-suppressor genes often behave as losers (Maruyama & Fujita, 2017; Morata & Calleja, 2020; Kanda & Igaki, 2020)." "Malignant tumors not only escape EDAC, but acquire properties that allow them to outcompete wildtype cells, facilitating invasion and metastasis (Suijkerbuijk et al., 2016; Kohashi et al., 2021)." "Evidence is accumulating that a human ortholog of Fmi, CELSR3, is expressed at high levels in a range of solid tumors, including lung, prostate, pancreatic, hepatic, ovarian and colorectal cancers, and in some cases has been shown to be associated with poor prognosis (Katoh & Katoh, 2007; Erkan et al., 2010; Asad et al., 2014; Goryca et al., 2018; Li et al., 2021; Chen et al., 2021a)."

Key Insights Distilled From

Flamingo participates in multiple models of cell competition

by Bosch,P. S.,... at www.biorxiv.org 09-24-2023

https://www.biorxiv.org/content/10.1101/2023.09.24.559197v2

Deeper Inquiries

How might the mechanism by which Fmi/CELSR promotes cell competition in tumors be leveraged for cancer therapy

The mechanism by which Fmi/CELSR promotes cell competition in tumors could potentially be leveraged for cancer therapy in several ways. One approach could involve targeting the signaling pathways downstream of Fmi/CELSR that are involved in promoting winner cell behavior. By identifying and inhibiting these pathways, it may be possible to disrupt the ability of tumor cells to outcompete healthy cells, thereby slowing down tumor growth and invasion. Additionally, understanding the specific ligands that activate Fmi/CELSR in the context of cell competition could lead to the development of targeted therapies that block these interactions, preventing tumor cells from gaining a competitive advantage. Furthermore, exploring the role of Fmi/CELSR in mediating cell-cell communication between winner and loser cells could provide insights into novel therapeutic strategies that disrupt this communication and restore a balanced competitive environment within the tumor.

What other signaling pathways or cellular processes might interact with Fmi/CELSR to modulate its role in cell competition

Several signaling pathways and cellular processes may interact with Fmi/CELSR to modulate its role in cell competition. One potential interaction could involve the Hippo pathway, which is known to play a critical role in regulating cell proliferation, apoptosis, and tissue growth. Fmi/CELSR may crosstalk with the Hippo pathway to coordinate cell competition outcomes by influencing the balance between winner and loser cells. Additionally, interactions with the JNK signaling pathway, which is involved in apoptosis and cell elimination during cell competition, could further regulate the fate of competing cells. Other potential interactions may include the Wnt signaling pathway, which is implicated in cell fate determination and tissue homeostasis, and the Notch signaling pathway, which regulates cell-cell communication and differentiation. Understanding how Fmi/CELSR interacts with these pathways and processes could provide valuable insights into the mechanisms underlying cell competition and its implications for cancer therapy.

Given the diverse functions of Fmi/CELSR in development, how might its role in cell competition be integrated with its other known roles, such as in axon guidance and dendrite tiling

The diverse functions of Fmi/CELSR in development, such as in axon guidance and dendrite tiling, may be integrated with its role in cell competition through shared signaling pathways and cellular processes. For example, the interactions between Fmi/CELSR and core PCP proteins in the context of axon guidance and dendrite tiling could also influence cell competition outcomes by regulating cell polarity and cell-cell communication. Additionally, the involvement of Fmi/CELSR in mediating adhesion and signaling events during axon guidance and dendrite tiling may contribute to its role in promoting winner cell behavior in cell competition. By integrating these various functions, Fmi/CELSR could act as a central regulator of cell fitness and competitive interactions, orchestrating the balance between winner and loser cells in both developmental processes and tumorigenesis.