The Hippo signaling mechanism, the newest member of the family of signaling pathways known to regulate organ size and development, is an evolutionarily conserved signaling mechanism. The evolutionary conserved serine/threonine kinase signaling cascade known as the Hippo pathway was first discovered in fruit flies (Drosophila melanogaster). Hippo signaling has been shown to be important in controlling cell proliferation and accelerating the development of several diseaes, including cancer. Numerous studies have demonstrated that, in addition to its well-known responsibilities in regulating cell proliferation and cell death, the Hippo pathway also serves as a critical mechanotransducer to detect mechanical alterations in the surroundings. It is still unclear how mechanical stimuli are transmitted from plasma membrane-localized receptors to activate Hippo signaling cascade-mediated cellular responses, particularly in intact tissues, despite the identification of numerous essential mechanosensitive signaling molecules like RAP2, MAP4K, Agrin, and Spectrin. In order to preserve tissue homeostasis, tumor-suppressive cell competition is an evolutionarily conserved process that destroys precancerous cells in a targeted manner.
In a new study published in Cell Reports, Westlake University researchers Du Kong, Sihua Zhao, Dr. Wenyan Xu, Jinxi Dong, and Professor Xianjue Ma discovered a new regulatory mechanism in which mechanical tension stimulates tumor-suppressive cell competition through the Hippo pathway. They identified Toll-6, a member of the Toll-like receptor family, as the driver of tension-mediated cell competition through the a-Spectrin (a-Spec)-Yorkie (Yki) cascade using the polarity-deficiency-induced cell competition paradigm in Drosophila. Moreover, the researchers showed that fat body (FB)-derived Spz5 are a vital ligand and further established that inter-organ communication is essential for eliminating precancerous cells at a systemic level.
The authors’ findings show that tension-dependent cell competition eliminates polarity-deficient oncogenic clones, and they also identify Toll-6 as a crucial membrane receptor that physically interacts with and activates the Hippo pathway through a-Spec. Data from their study revealed that scrib clones accumulate and are made easier to get rid of by two crucial cytoskeleton regulators, a-Spec and Rho1. Additionally, authors discovered that a-Spec serves as an essential linker between tensional changes brought on by Toll-6 activation and cytosolic Hippo circuit activation. They demonstrated the critical role of Toll-6 in the regulation of tumor-suppressive cell competition as well as the mechanism by which the Toll-6-a-Spec axis initiates the mechanical tension-mediated Hippo cascade from the cell membrane. Notably, they discovered that Myc-induced cell competition might occur without Toll-6. It may be possible to gain an in vivo mechanistic understanding of the inter-organ communications between FBs and remotely colonized precancerous clones from their findings that the transcription of spz5 is increased in the FB from scrib clone containing larvae to enable tumor-suppressive cell competition. Together, the available data lend credence to the idea that scrib/ clones induce autonomous Toll-6 accumulation (through an unidentified mechanism) near the winner-loser divide, which attracts a-Spec and causes Hippo pathway-dependent elimination of scrib/ clones.
Future experiments will focus on explaining the molecular mechanisms by which Toll-6 recruits a-Spec and starts the downstream signaling transduction. The research team reported that FB-derived Spz5 is necessary for eradicating scrib mutant clones via inter-organ communications, it will be important in the future to learn exactly how the spz5 mRNA level is systematically increased in the FBs of larvae carrying scrib mutant clones.
In summary, Professor Xianjue Ma and his colleagues employed a polarity-deficiency-induced cell competition model to demonstrate how loser clones are removed by actomyosin-dependent Hippo pathway activation. The authors show that Spz5 produced from fat bodies accelerated the eradication of the loser clones and identified Toll-6 as an important membrane receptor that actively eliminates losers via the cytoskeletal network.
Kong D, Zhao S, Xu W, Dong J, Ma X. Fat body-derived Spz5 remotely facilitates tumor-suppressive cell competition through Toll-6-α-Spectrin axis-mediated Hippo activation. Cell Reports. 2022 Jun 21;39(12):110980.