Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways.

Hormone therapy resistance and the ensuing aggressive tumor progression present a significant clinical challenge. However, the mechanisms underlying the induction of tumor malignancy upon inhibition of steroid hormone signaling remain poorly understood. Here, we demonstrate that Drosophila malignant epithelial tumors show a similar reduction in ecdysone signaling, the main steroid hormone pathway.

The divergent effects of G3BP orthologs on human stress granule assembly imply a centric role for the core protein interaction network.

Liquid-liquid phase separation (LLPS) mediated by G3BP1/2 proteins and non-translating mRNAs mediates stress granule (SG) assembly. We investigated the phylogenetic evolution of G3BP orthologs from unicellular yeast to mammals and identified both conserved and divergent features. The modular domain organization of G3BP orthologs is generally conserved.

Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.

The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals.

Q&A with Xianjue Ma.

We at Cell Reports discuss with Xianjue Ma his work on mechanisms of tumor progression, particularly his lab's recent work on tumor-suppressive cell competition.

Differential Ire1 determines loser cell fate in tumor-suppressive cell competition.

Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the Ire1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC.

E2 enzyme Bruce negatively regulates Hippo signaling through POSH-mediated expanded degradation.

The Hippo pathway is a master regulator of organ growth, stem cell renewal, and tumorigenesis, its activation is tightly controlled by various post-translational modifications, including ubiquitination. While several E3 ubiquitin ligases have been identified as regulators of Hippo pathway, the corresponding E2 ubiquitin-conjugating enzymes (E2s) remain unknown. Here, we performed a screen in Drosophila to identify E2s involved in regulating wing overgrowth caused by the overexpression of Crumbs (Crb) intracellular domain and identified Bruce as a critical regulator.

Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria.

Maternal age at childbearing has continued to increase in recent decades. However, whether and how it influences offspring adult traits are largely unknown. Here, using adult body size as the primary readout, we reveal that maternal rather than paternal age has an evolutionarily conserved effect on offspring adult traits in humans, Drosophila, and Caenorhabditis elegans.

Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner.

Mechanistic insights and implications of FOXO-SNAI interplay.

Autophagy promotes both health and disease, depending on tissue types and genetic contexts, yet the regulatory mechanism remain incompletely understood. Our recent publication has uncovered a coherent FOXO-SNAI feed-forward loop in autophagy, which is evolutionarily conserved from Drosophila to human. In addition, it's revealed that DNA binding plays a critical role in intracellular localization of nucleocytoplasmic shuttling proteins.

Fat body-derived Spz5 remotely facilitates tumor-suppressive cell competition through Toll-6-α-Spectrin axis-mediated Hippo activation.

Tumor-suppressive cell competition is an evolutionarily conserved process that selectively removes precancerous cells to maintain tissue homeostasis. Using the polarity-deficiency-induced cell competition model in Drosophila, we identify Toll-6, a Toll-like receptor family member, as a driver of tension-mediated cell competition through α-Spectrin (α-Spec)-Yorkie (Yki) cascade. Toll-6 aggregates along the boundary between wild-type and polarity-deficient clones, where Toll-6 physically interacts with the cytoskeleton network protein α-Spec to increase mechanical tension, resulting in actomyosin-dependent Hippo pathway activation and the elimination of scrib mutant cells.

A conserved interplay between FOXO and SNAI/snail in autophagy.

Dysfunction of macroautophagy/autophagy has been implicated in homeostasis maintenance and contributes to various diseases. Yet the mechanisms that regulate autophagy have not been fully understood. In a recent study, we uncovered a coherent FOXO3-SNAI2 feed-forward regulatory loop in mammals that reinforces autophagy gene induction upon energy stress.

A coherent FOXO3-SNAI2 feed-forward loop in autophagy.

SignificanceUnderstanding autophagy regulation is instrumental in developing therapeutic interventions for autophagy-associated disease. Here, we identified SNAI2 as a regulator of autophagy from a genome-wide screen in HeLa cells. Upon energy stress, SNAI2 is transcriptionally activated by FOXO3 and interacts with FOXO3 to form a feed-forward regulatory loop to reinforce the expression of autophagy genes.

Myc suppresses male-male courtship in Drosophila.

Despite strong natural selection on species, same-sex sexual attraction is widespread across animals, yet the underlying mechanisms remain elusive. Here, we report that the proto-oncogene Myc is required in dopaminergic neurons to inhibit Drosophila male-male courtship. Loss of Myc, either by mutation or neuro-specific knockdown, induced males' courtship propensity toward other males.

Low-density-lipoprotein-receptor-related protein 1 mediates Notch pathway activation.

The Notch signaling pathway controls cell growth, differentiation, and fate decisions, and its dysregulation has been linked to various human genetic disorders and cancers. To comprehensively understand the global organization of the Notch pathway and identify potential drug targets for Notch-related diseases, we established a protein interaction landscape for the human Notch pathway. By combining and analyzing genetic and phenotypic data with bioinformatics analysis, we greatly expanded this pathway and identified many key regulators, including low-density-lipoprotein-receptor-related protein 1 (LRP1).

Wallenda-Nmo Axis Regulates Growth via Hippo Signaling.

Both Hippo signaling pathways and cell polarity regulation are critical for cell proliferation and the maintenance of tissue homeostasis, despite the well-established connections between cell polarity disruption and Hippo inactivation, the molecular mechanism by which aberrant cell polarity induces Hippo-mediated overgrowth remains underexplored. Here we use wing discs as a model and identify the Wnd-Nmo axis as an important molecular link that bridges loss-of-cell polarity-triggered Hippo inactivation and overgrowth. We show that Wallenda (Wnd), a MAPKKK (mitogen-activated protein kinase kinase kinase) family member, is a novel regulator of Hippo pathways in and that overexpression of Wnd promotes growth via Nemo (Nmo)- mediated Hippo pathway inactivation.

Misshapen Disruption Cooperates with to Drive Tumorigenesis.

Although family genes play essential roles in tumorigenesis, effective treatments targeting -related tumors are lacking, partly because of an incomplete understanding of the complex signaling crosstalk within -related tumors. Here, we performed a large-scale genetic screen in eye imaginal discs and identified () as a tumor suppressor that synergizes with oncogenic () to induce c-Jun N-terminal kinase (JNK) activation and Hippo inactivation, then subsequently leads to tumor overgrowth and invasion. Moreover, ectopic Msn expression activates Hippo signaling pathway and suppresses Hippo signaling disruption-induced overgrowth.

Rox8 promotes microRNA-dependent messenger RNA decay.

The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In , oncogenic Ras cooperates with loss-of-cell polarity to promote Hippo pathway-dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway.

A novel regulator of ER Ca drives Hippo-mediated tumorigenesis.

Calcium ion (Ca) is a versatile second messenger that regulates various cellular and physiological functions. However, the in vivo molecular mechanisms by which Ca alterations contribute to tumor growth remain poorly explored. Here we show that Emei is a novel ER Ca regulator that synergizes with Ras to induce tumor growth via JNK-mediated Hippo signaling.

Spz/Toll-6 signal guides organotropic metastasis in .

Targeted cell migration plays important roles in developmental biology and disease processes, including in metastasis. tumors exhibit traits characteristic of human cancers, providing a powerful model to study developmental and cancer biology. We now find that cells derived from eye-disc tumors also display organ-specific metastasis, invading receptive organs but not wing disc.

Wingless modulates activator protein-1-mediated tumor invasion.

Metastasis begins with a subset of local tumor cells acquiring the potential to invade into surrounding tissues, and remains to be a major obstacle for cancer treatments. More than 90% of cancer patients died from tumor metastasis, instead of primary tumor growth. The canonical Wnt/β-catenin pathway plays essential roles in promoting tumor formation, yet its function in regulating tumor metastasis and the underlying mechanisms remain controversial.

POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation.

The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in overexpression synergizes with loss of to induce overgrowth and up-regulation of Hippo pathway target genes.

PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion.

RAS genes are frequently mutated in cancers, yet an effective treatment has not been developed, partly because of an incomplete understanding of signaling within Ras-related tumors. To address this, we performed a genetic screen in Drosophila, aiming to find mutations that cooperate with oncogenic Ras (Ras) to induce tumor overgrowth and invasion. We identified fiery mountain (fmt), a regulatory subunit of the protein phosphatase 6 (PP6) complex, as a tumor suppressor that synergizes with Ras to drive c-Jun N-terminal kinase (JNK)-dependent tumor growth and invasiveness.

The dark side of hippo signaling: A cancer promoter role.

The Hippo signaling pathway regulates organ size and tissue homeostasis. Given this role it is unsurprising that dysregulation of this pathway has implications for cancer progression. A convincing body of literature shows that the Hippo pathway serves a tumor suppressive function with its inactivation leading to massive overgrowth.