Hippo signaling pathway

Hippo signaling pathway

Hippo signaling pathway, also known as the Salvador/Warts/Hippo (SWH) pathway, controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue overgrowth, or a “hippopotamus”-like phenotype.

A fundamental question in developmental biology is how an organ knows to stop growing after reaching a particular size. Organ growth relies on several processes occurring at the cellular level, including cell division and programmed cell death (or apoptosis). The Hippo signaling pathway is involved in restraining cell proliferation and promoting apoptosis. As many cancers are marked by unchecked cell division, this signaling pathway has become increasingly significant in the study of human cancer.

The Hippo signaling pathway appears to be highly conserved. While most of the Hippo pathway components were identified in the fruit fly (Drosophila melanogaster) using mosaic genetic screens, orthologs to these components (genes that function analogously in different species) have subsequently been found in mammals. Thus, the delineation of the pathway in Drosophila has helped to identify many genes that function as oncogenes or tumor suppressors in mammals.


Results showed the overexpression of YAP1 and Survivin as well as a decreased activity of large tumor suppressor 1 (LATS1) in high-grade glioblastoma versus anaplastic astrocytoma and low-grade glioma. Furthermore, Aguennouz et al. also demonstrated that miR-221 and miR-10b are specifically involved in Hippo signaling pathway via LATS1 regulation and that their knockdown significantly decreased glioma cell proliferation. This preliminary data confirmed the crucial role of the Hippo signaling pathway in cancer and suggested that miR 221 and miR 10b could be potential therapeutic targets for glioma treatment 1).


Increasing studies have revealed that metabolic disorders, especially diabetes, are high risk factors for the development of Alzheimer’s disease (AD) and other neurodegenerative diseases. It has been reported that patients with diabetes are prone to suffer from cognitive dysfunction (CD). Although abnormal glucose metabolism and deposition of amyloid β (Aβ) are proven to have a closely relationship with diabetes-induced CD, its exact mechanism is still undetermined. In this study, a total of 14 mice were intraperitoneally injected with streptozotocin for 5 consecutive days to mimic diabetic models, and then hierarchical cluster analysis was adopted to classify the diabetic mice into CD and Non-CD phenotypes by the results of Morris water maze test (MWMT). Furthermore, we detected Hippo signaling including mammalian sterile 20-like protein kinases1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP) and phosphorylation of YAP (p-YAP) in brain and peripheral tissues. As compared with control mice, the levels of MST1, LATS1 and p-YAP/YAP ratio were increased in medial prefrontal cortex (mPFC), striatum and hippocampus of CD mice, while these proteins were decreased in gut tissue of CD mice. Additionally, there were significant positive correlations between escape latency and p-YAP/YAP ratio in mPFC, anterior cingulate cortex (ACC) and hippocampus, as well as the level of LATS1 in liver, kidney and gut tissues. In conclusion, alterations in Hippo signaling may contribute to CD induced by diabetes. Therefore, therapeutic interventions improving Hippo signaling might be beneficial to the treatment of diabetes-induced CD and other neurodegenerative diseases 2).


The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals, and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are composed of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4, and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers, and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas, and the NF2 gene product, Merlin, acts upstream of the Hippo pathway. Baia et al. show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using an siRNA transient knockdown of YAP1 in NF2-mutant meningioma cells, they show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas, deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis 3).


Physiologically, The Hippo signaling largely restricts its two downstream effectors, homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), to a low level of activity by the MST1-SAV1 complex-induced kinase cascade. However, how the negative regulation induced by MST1-SAV1 complex is disrupted to exhibit constitutive YAP/TAZ activation in cancer remains unclear.

Zhu et al.report that miR-130b directly repressed MST1 and SAV1 expression in human glioblastoma cells. Overexpression of miR-130b induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF and the pluripotency associated markers, including CD133, SOX2, Nanog, MYC and BMI1, leading to promotion of glioblastoma stem cell phenotype. Conversely, inhibition of miR-130b attenuated these effects. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-130b in the progression of glioblastoma, but also may represent a new therapeutic target 4).

References

1)

Aguennouz M, Polito F, Visalli M, et al. microRNA-10 and -221 modulate differential expression of Hippo signaling pathway in human astroglial tumors [published online ahead of print, 2020 Aug 5]. Cancer Treat Res Commun. 2020;24:100203. doi:10.1016/j.ctarc.2020.100203
2)

Yu F, Han W, Zhan G, Li S, Jiang X, Xiang S, Zhu B, Yang L, Hua D, Luo A, Hua F, Yang C. Differential Levels of Hippo Signaling in Selected Brain and Peripheral Tissues in Streptozotocin-Induced Cognitive Dysfunction in Mice. Neuroscience. 2019 Nov 1. pii: S0306-4522(19)30663-3. doi: 10.1016/j.neuroscience.2019.09.018. [Epub ahead of print] PubMed PMID: 31682826.
3)

Baia GS, Caballero OL, Orr BA, Lal A, Ho JS, Cowdrey C, Tihan T, Mawrin C, Riggins GJ. Yes-associated protein 1 is activated and functions as an oncogene in meningiomas. Mol Cancer Res. 2012 Jul;10(7):904-13. doi: 10.1158/1541-7786.MCR-12-0116. Epub 2012 May 22. PubMed PMID: 22618028.
4)

Zhu G, Wang Y, Mijiti M, Wang Z, Wu PF, Jiafu D. Upregulation of miR-130b enhances stem cell-like phenotype in glioblastoma by inactivating the Hippo signaling pathway. Biochem Biophys Res Commun. 2015 Aug 1. pii: S0006-291X(15)30379-X. doi: 10.1016/j.bbrc.2015.07.149. [Epub ahead of print] PubMed PMID: 26241672.

Subthalamic deep brain stimulation for Parkinson’s disease outcome

Subthalamic deep brain stimulation for Parkinson’s disease outcome

The surgical and clinical outcomes of asleep DBS for Parkinson’s disease are comparable to those of awake DBS 1).


Suboptimal targeting within the STN can give rise to intolerable sensorimotor side effects, such as dysarthria, contractions and paresthesias 2) 3) 4). eye movement perturbations, and psychiatric symptoms 5) 6) 7), limiting the management of motor symptoms. The small size of the STN motor territory and the consequences of spreading current to immediately adjacent structures obligate precise targeting. Neurosurgeons therefore rely on a combination of imaging, electrophysiology, kinesthetic responses, and stimulation testing to accurately place the DBS lead into the sensorimotor domain of STN 8) 9) 10).

Deep Brain Stimulation has been associated with post-operative neuropsychology changes, especially in verbal memory.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) is widely accepted to treat advanced Parkinson disease (PD). However, published studies were mainly conducted in Western centers 11).

High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson’s disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony.

Low-frequency stimulation of the subthalamic nucleus via the optimal contacts is effective in improving overall motor function of patients with Parkinson Disease 12). In Parkinson’s disease significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. Sobstyl et al., demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and Unified Dyskinesia Rating Scale in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores 13).

The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement.

A study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes 14).


Although dementia is a contraindication in deep brain stimulation for Parkinson’s disease, the concept is supported by little scientific evidence. Moreover, it is unclear whether PD with mild cognitive impairment (PD-MCI) or domain-specific cognitive impairments affect the outcome of DBS in non-demented PD patients.

Baseline cognitive levels of patients with PD who underwent DBS were classified into PD with dementia (PDD) (n = 15), PD-MCI (n = 210), and normal cognition (PD-NC) (n = 79). The impact of the cognitive level on key DBS outcome measures [mortality, nursing home admission, progression to Hoehn&Yahr (HY) stage 5 and progression to PDD] were analyzed using Cox regression models. Park et al. also investigated whether impairment of a specific cognitive domain could predict these outcomes in non-demented patients.

Results: Patients with PDD showed a substantially higher risk of nursing home admission and progression to HY stage 5 compared with patients with PD-MCI [hazard ratio (HR) 4.20, P = .002; HR = 5.29, P < .001] and PD-NC (HR 7.50, P < .001; HR = 7.93, P < .001). MCI did not alter the prognosis in patients without dementia, but those with visuospatial impairment showed poorer outcomes for nursing home admission (P = .015), progression to HY stage 5 (P = .027) and PDD (P = .006).

Conclusions: Cognitive profiles may stratify the pre-operative risk and predict long-term outcomes of DBS in PD 15).

References

1)

Wang J, Ponce FA, Tao J, Yu HM, Liu JY, Wang YJ, Luan GM, Ou SW. Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson’s Disease: A Detailed Analysis Through Literature Review. Neuromodulation. 2019 Dec 12. doi: 10.1111/ner.13061. [Epub ahead of print] Review. PubMed PMID: 31830772.
2) , 9)

Benabid AL, Chabardes S, Mitrofanis J, Pollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81, 2009
3) , 10)

Groiss SJ, Wojtecki L, Südmeyer M, Schnitzler A: Deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disorder 2:20–28, 2009
4)

Zhang S, Zhou P, Jiang S, Wang W, Li P: Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease: a report of 12 cases. Medicine (Baltimore) 95:e5575, 2016
5)

Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J, Parés P: Mania following deep brain stimulation for Parkinson’s disease. Neurology 59:1421–1424, 2002
6)

Mallet L, Schüpbach M, N’Diaye K, Remy P, Bardinet E, Czernecki V, et al: Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc Natl Acad Sci U S A 104:10661–10666, 2007
7)

Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F: Manic episode with psychotic symptoms in a patient with Parkinson’s disease treated by subthalamic nucleus stimulation: improvement on switching the target. J Neurol Sci 273:116–117, 2008
8)

Abosch A, Timmermann L, Bartley S, Rietkerk HG, Whiting D, Connolly PJ, et al: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1–11, 2013
11)

Chiou SM, Lin YC, Huang HM. One-year Outcome of Bilateral Subthalamic Stimulation in Parkinson Disease: An Eastern Experience. World Neurosurg. 2015 Jun 10. pii: S1878-8750(15)00709-3. doi: 0.1016/j.wneu.2015.06.002. [Epub ahead of print] PubMed PMID: 26072454.
12)

Khoo HM, Kishima H, Hosomi K, Maruo T, Tani N, Oshino S, Shimokawa T, Yokoe M, Mochizuki H, Saitoh Y, Yoshimine T. Low-frequency subthalamic nucleus stimulation in Parkinson’s disease: A randomized clinical trial. Mov Disord. 2014 Jan 21. doi: 10.1002/mds.25810. [Epub ahead of print] PubMed PMID: 24449169.
13)

Sobstyl M, Ząbek M, Górecki W, Mossakowski Z. Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study. Clin Neurol Neurosurg. 2014 Sep;124:161-5. doi: 10.1016/j.clineuro.2014.06.019. Epub 2014 Jun 23. PubMed PMID: 25051167.
14)

Cui Z, Pan L, Song H, Xu X, Xu B, Yu X, Ling Z. Intraoperative MRI for optimizing electrode placement for deep brain stimulation of the subthalamic nucleus in Parkinson disease. J Neurosurg. 2016 Jan;124(1):62-9. doi: 10.3171/2015.1.JNS141534. Epub 2015 Aug 14. PubMed PMID: 26274983.
15)

Park KW, Jo S, Kim MS, et al. Cognitive profile as a predictor of the long-term outcome after deep brain stimulation in Parkinson’s disease [published online ahead of print, 2020 Jul 28]. J Neurol Sci. 2020;417:117063. doi:10.1016/j.jns.2020.117063

Glioma tumor microenvironment

Glioma tumor microenvironment

In a study, both U118 cell and GSC23 cell exhibited good printability and cell proliferation. Compared with 3D-U118, 3D-GSC23 had a greater ability to form cell spheroids, to secrete VEGFA, and to form tubule-like structures in vitro. More importantly, 3D-GSC23 cells had a greater power to transdifferentiate into functional endothelial cells, and blood vessels composed of tumor cells with an abnormal endothelial phenotype was observed in vivo. In summary, 3D bioprinted hydrogel scaffold provided a suitable tumor microenvironment (TME) for glioma cells and GSCs. This bioprinted model supported a novel TME for the research of glioma cells, especially GSCs in glioma vascularization and therapeutic targeting of tumor angiogenesis 1).


Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. Jeanmougin et al. investigated the abundance of infiltrating immune and stromal cellin silico, from gene expression profiles. Two cohorts, including in-house normal brain and glioma samples (n=70) and a large sample set from The Cancer Genome Atlas (TCGA)(n=393), were combined into a single exploratory dataset. A third independent cohort (n=124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. Jeanmougin et al. identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that the tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes to improving prognostic models in GBM 2).


Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression and therapy resistance.

This resiliency of glioma stem cells (GSCs) is, in part, due to self-remodeling of their supportive niche also known as the tumor microenvironment 3) 4) 5) 6).

The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The tumor microenvironment contributes to tumour heterogeneity.

Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms.

Solid cancers develop in dynamically modified microenvironments in which they seem to hijack resident and infiltrating nontumor cells, and exploit existing extracellular matrices and interstitial fluids for their own benefit. Glioblastoma (GBM), the most malignant intrinsic glial brain tumor, hardly colonizes niches outside the central nervous system (CNS). It seems to need the unique composition of cranial microenvironment for growth and invasion as the incidence of extracranial metastasis of GBM is as low as 0.5%. Different nontumor cells (both infiltrating and resident), structures and substances constitute a semiprotected environment, partially behind the well-known blood–brain barrier, benefitting from the relatively immune privileged state of the CNS. This imposes a particular challenge on researchers and clinicians who try to tackle this disease and desire to penetrate efficiently into this shielded environment to weaken the GBM cells and cut them off from the Hinterland they are addicted to. In this chapter, we focus on how GBM interacts with the different components of its tumor microenvironment (TME), how we can target this TME as a useful contribution to the existing treatments, how we could make further progress in our understanding and interaction with this environment as a crucial step toward a better disease control in the future, and what efforts have already been taken thus far 7).


To characterize the glioma tumor microenvironment, a mixed collective of nine glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]FET-PET-MRI. Image-guided biopsy samples were immuno-phenotyped by multiparameter flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity.

They found a strong relationship (r = 0.84, p = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to HLA-DR+ activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714-positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution.

[18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME. 8).

References

1)

Wang X, Li X, Ding J, et al. 3D bioprinted glioma microenvironment for glioma vascularization [published online ahead of print, 2020 Aug 10]. J Biomed Mater Res A. 2020;10.1002/jbm.a.37082. doi:10.1002/jbm.a.37082
2)

Jeanmougin M, Håvik AB, Cekaite L, Brandal P, Sveen A, Meling TR, Ågesen TH, Scheie D, Heim S, Lothe RA, Lind GE. Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment. Mol Oncol. 2020 Mar 14. doi: 10.1002/1878-0261.12668. [Epub ahead of print] PubMed PMID: 32171051.
3)

Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69-82.
4)

Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139- 152.
5)

Lathia JD, Heddleston JM, Venere M, et al. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8(5):482- 485.
6)

Wang L, Rahn JJ, Lun X, et al. Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor. PLoS Biol. 2008;6(11):e289.
7)

De Vleeschouwer S, Bergers G. Glioblastoma: To Target the Tumor Cell or the Microenvironment? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 16. Available from http://www.ncbi.nlm.nih.gov/books/NBK469984/ PubMed PMID: 29251862.
8)

Zinnhardt B, Müther M, Roll W, Backhaus P, Jeibmann A, Foray C, Barca C, Döring C, Tavitian B, Dollé F, Weckesser M, Winkeler A, Hermann S, Wagner S, Wiendl H, Stummer W, Jacobs AH, Schäfers M, Grauer OM. TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma. Neuro Oncol. 2020 Feb 12. pii: noaa023. doi: 10.1093/neuonc/noaa023. [Epub ahead of print] PubMed PMID: 32047908.
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