Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1078848 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28035352_1.fastq.gz | Fastqsanger.gz | |||
| SRR28035352_2.fastq.gz | Fastqsanger.gz | |||
| SRR28035353_1.fastq.gz | Fastqsanger.gz | |||
| SRR28035353_2.fastq.gz | Fastqsanger.gz | |||
| SRR28035354_1.fastq.gz | Fastqsanger.gz |
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Project description:We have discovered a previously uncharacterized tumor suppressor function of Numb in the homeostasis of the normal bladder mucosa. Targeted ablation of Numb in the basal layer of the urothelium drives spontaneous bladder tumorigenesis, driving progression from preneoplastic to preinvasive and overtly invasive tumors, and accelerates tumorigenesis in the presence of oncogenic insults. Using 3D-Matrigel organoid cultures to recapitulate bladder tumorigenesis in vitro, we found that Numb deficiency enhances the proliferative and invasive potential of both mouse and human bladder cancer cells. Integrative transcriptomic and functional analyses revealed that downregulation of the canonical Hippo pathway, resulting in enhanced YAP transcriptional activity, underlies the biological aggressiveness of Numb-deficient bladder cancer. These molecular events are dependent on the activation of RhoA/ROCK signaling subsequent to Numb loss. Thus, a dysfunctional Numb–RhoA/ROCK–Hippo/YAP regulatory network is at play in aggressive Numb-deficient bladder cancers, opening avenues for the development of targeted therapies. Furthermore, retrospective cohort studies revealed that a Numb-deficient status correlates with worse overall survival in post-cystectomy muscle-invasive bladder cancer (MIBC) patients and increased risk of progression to MIBC in non-muscle-invasive bladder cancer (NMIBC) patients. The Numb-deficient status was associated with a 27-gene prognostic signature that has the potential to identify high-risk NMIBC patients who are eligible for targeted RhoA/ROCK/YAP therapies.
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Project description:Lymphatic drainage generates force that induces prostate cancer cell motility via activation of Yes-associated protein (YAP), but whether this response to fluid force is conserved across cancer types is unclear. Here, we show that shear stress corresponding to fluid flow in the initial lymphatics modifies taxis in breast cancer. Whereas some cell lines employ rapid amoeboid migration behavior in response to fluid flow, a separate subset decrease movement. Positive responders displayed transcriptional profiles typical of an amoeboid cell state. Regulation of the HIPPO tumor suppressor pathway and YAP activity also differed between breast subsets and prostate cancer. Although subcellular localization of YAP to the nucleus positively correlated with overall velocity of locomotion, YAP gain- and loss-of-function demonstrates that YAP inhibits breast cancer motility but is outcompeted by other pro-taxis mediators in the context of flow. Specifically, we show that RhoA dictates response to flow. GTPase activity of RhoA, but not Rac1 or Cdc42 Rho family GTPases, is elevated in cells that positively respond to flow and is unchanged in cells that decelerate under flow. Disruption of RhoA or the RhoA effector, Rho-associated kinase (ROCK), blocked shear stress-induced motility. Collectively, these findings demonstrate stratification of breast cancer subsets by flow-sensing mechanotransduction pathways and point to a role for biophysical force in regulation of an amoeboid cell state.
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Project description:Mesenchymal stem cells (MSCs) participate in the repair/remodeling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFβ-activated RhoA/ROCK functions as a molecular switch regarding the fate of MSCs in arterial repair/remodeling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell-ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration.
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Project description:In this study, our research focused on investigating the impact of Anlotinib in enhancing the tumor targeting of antitumor drugs in vivo. Through RNA-sequencing and Label-free quantitative proteomics analysis, we discovered that Anlotinib effectively regulated the expression of extracellular matrix (ECM) genes and proteins, leading to a significant reduction in ECM stiffness. Our bioinformatic analysis indicated a potential positive relationship between the ECM pathways and gefitinib resistance, poor PD-1 treatment outcomes, as well as unfavorable prognosis in lung cancer patients following chemotherapy. To evaluate the efficacy of Anlotinib, we administered it in combination with anti-PD-1/PD-L1 agents, chemotherapeutic drugs, and gefitinib, and visualized their distribution using fluorescent labeling in various tumor types. Notably, our results demonstrated that Anlotinib substantially improved the drug targeting process by prolonging the retention time of antitumor drugs at the tumor site. Moreover, the combination therapy induced a notable loosening of the tumor tissue structure compared to the control group. This reduction in stiffness was further associated with decreased interstitial fluid pressures and tumor solid pressure. Additionally, we observed that Anlotinib effectively suppressed the RhoA/ROCK signaling pathway, inhibiting the formation of stress fibers. These findings strongly suggest that Anlotinib enhances the distribution and retention of antitumor drugs in tumors by modulating ECM expression and physical properties through the RhoA/ROCK signaling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumor targeting in cancer treatment.
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Project description:The small GTPase RhoA regulates a variety of cellular processes, including cell motility, proliferation, survival and permeability. In addition, there are reports suggesting that the RhoA-ROCK axis plays a role in VEGF-mediated angiogenesis, whereas other work has shown opposite effects. To elucidate this conflicting data, we examined HUVEC and HCAEC after stable overexpression (lentiviral transduction) of constitutively active (G14V/Q63L), dominant-negative (T19N), or wild-type RhoA using a variety of in vitro angiogenesis assays (proliferation, migration, tube formation, angiogenic sprouting, endothelial cell viability) and a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. We observed that expression of active as well as wild-type RhoA but not expression of dominant-negative RhoA significantly increased endothelial cell death as well as inhibited endothelial cell proliferation, migration, tube formation and angiogenic sprouting of endothelial cells in vitro and reduced HUVEC-related angiogenesis in vivo. Inhibition of RhoA by C3 transferase antagonized inhibitory RhoA effects and strongly enhanced VEGF-induced angiogenic sprouting in control-treated cells. In contrast, inhibition of RhoA effectors ROCK1/2 and LIMK1/2 had no significant effect on RhoA-related effects, but again increased angiogenic sprouting and migration of control-treated cells. In line with these data, VEGF did not activate RhoA in HUVEC as measured by a FRET-based biosensor. Furthermore, global transcriptome and subsequent bioinformatic gene ontology (GO) enrichment analyses revealed that constitutively active RhoA induces a differentially expressed gene pattern that is enriched for GO biological process terms such as mitotic nuclear division, cell proliferation, cell motility and cell adhesion and includes a significant decrease in VEGFR-2 and NOS3 expression. Thus, our data demonstrate that increased RhoA activity has the potential to trigger endothelial dysfunction and anti-angiogenic effects independently of its well-characterized downstream effectors ROCK and LIMK.
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Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.
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Project description:Mesenchymal stem cells (MSCs) participate in the repair/remodeling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFβ-activated RhoA/ROCK functions as a molecular switch regarding the fate of MSCs in arterial repair/remodeling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell-ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration. Mouse bone marrow MSCs were purchased from Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine. All MSCs were cultured in αMEM supplied with 10% FCS. The transfection of DNA plasmids were performed with Lipofectamine® LTX with Plus Reagent (Life Technologies). Myc-L63RhoA or empty vector (control) was transfected into mouse bone marrow MSCs. Three days later, the cells were harvested and total RNA was isolated using RNeasy Mini kit (Qiagen). A total of four independent experiments were performed. RNA samples were assessed for quality and integrity using Synergy HT (Biotek, Winooski, VT). Microarray expression profiles were generated using the Illumina MouseRef-8 v2.0 Expression BeadChip (Illumina, San Diego, CA). Biotin-labeled cRNA was synthesized by the total prep RNA amplification kit from Ambion (Austin, TX). cRNA was quantified and normalized to 75 ng/µl, and then 1µg was hybridized to Beadchips. The hybridized chip was scanned using the Illumina iScan system and background corrected signal intensities were extracted using the GenomeStudio software (Illumina). The lumi R package was used to transform the data using a Variance Stabilizing Transformation (VST) and normalized using quantile normalization. Differential expression analysis was performed using the R/Mannova package. P-values were calculated by performing 1000 permutations, then corrected for multiple comparisons by false-discovery rate (FDR) transformation, using a 20% FDR cutoff.
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