scholarly journals Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1908
Author(s):  
Anke Koeniger ◽  
Anna Brichkina ◽  
Iris Nee ◽  
Lukas Dempwolff ◽  
Anna Hupfer ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Survival Rates ◽  
Genetic Alterations ◽  
Novel Therapy ◽  
Therapeutic Concept ◽  
Pathway Activation ◽  
Starting Point ◽  
Novel Concept ◽  
Neural Crest Differentiation

Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain genetic alterations, 5-year survival rates can drop below 30%, necessitating the development of novel therapy approaches. The developmentally important Hedgehog (Hh) pathway is involved in neural crest differentiation, the cell type being causal in the etiology of NB. However, and in contrast to its function in some other cancer types, Hedgehog signaling and its transcription factor GLI1 exert tumor-suppressive functions in NB, rendering GLI1 an interesting new candidate for anti-NB therapy. Unfortunately, the therapeutic concept of pharmacological Hh/GLI1 pathway activation is difficult to implement as NB cells have lost primary cilia, essential organelles for Hh perception and activation. In order to bypass this bottleneck, we have identified a GLI1-activating small molecule which stimulates endogenous GLI1 production without the need for upstream Hh pathway elements such as Smoothened or primary cilia. This isoxazole compound potently abrogates NB cell proliferation and might serve as a starting point for the development of a novel class of NB-suppressive molecules.

scholarly journals KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Petra Pejskova ◽  
Madeline Louise Reilly ◽  
Lucia Bino ◽  
Ondrej Bernatik ◽  
Linda Dolanska ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Cell Cycle Progression ◽  
Primary Cilia ◽  
Aurora A ◽  
Pathway Activation ◽  
Cilia Formation ◽  
Tightly Coupled ◽  
Hh Signaling

Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

scholarly journals Plexins Promote Hedgehog Signaling Through Their Cytoplasmic GAP Activity

2021 ◽  
Author(s):  
Justine M Pinskey ◽  
Tyler M Hoard ◽  
Xiao-Feng Zhao ◽  
Nicole E Franks ◽  
Zoe C Frank ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Hedgehog Pathway ◽  
Loss Of Function ◽  
3T3 Fibroblasts ◽  
Pathway Activation ◽  
Gli Transcription Factors ◽  
Full Complement ◽  
Positive Regulators ◽  
Nih 3T3

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified Neuropilins, established Semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require Plexin co-receptors to mediate Semaphorin signaling, but a role for Plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple Plexins promote Hedgehog signaling in NIH/3T3 fibroblasts and that Plexin loss-of-function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the Plexin GTPase activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that Plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that Plexin loss-of-function significantly reduces the response to Hedgehoga pathway activation in the mouse dentate gyrus. Together, these data identify Plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.

scholarly journals Time-resolved proteomic profiling of the ciliary Hedgehog response reveals that GPR161 and PKA undergo regulated co-exit from cilia

2020 ◽  
Author(s):  
Elena A. May ◽  
Marian Kalocsay ◽  
Inès Galtier D’Auriac ◽  
Steven P. Gygi ◽  
Maxence V. Nachury ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Regulatory Subunit ◽  
Proteomic Profiling ◽  
Time Resolved ◽  
Pathway Activation ◽  
Dependent Protein ◽  
A Cell ◽  
Cell Type Specific ◽  
Rapid Characterization

ABSTRACTThe primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the putative phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.

scholarly journals Time-resolved proteomics profiling of the ciliary Hedgehog response

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Elena A. May ◽  
Marian Kalocsay ◽  
Inès Galtier D’Auriac ◽  
Patrick S. Schuster ◽  
Steven P. Gygi ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Regulatory Subunit ◽  
Time Resolved ◽  
Pathway Activation ◽  
Dependent Protein ◽  
A Cell ◽  
Cell Type Specific ◽  
Rapid Characterization ◽  
G Protein Coupled

The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid, and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein–coupled receptor GPR161 in response to Hedgehog, and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type–specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.

scholarly journals Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients’ survival

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Woon Yong Jung ◽  
Kyueng-Whan Min ◽  
Young Ha Oh
Keyword(s):  
Immune Response ◽  
Survival Analysis ◽  
Lung Adenocarcinoma ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Enrichment Analysis ◽  
Genetic Alterations ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Solid Type

AbstractThe histological classification of lung adenocarcinoma includes 5 types: lepidic, acinar, papillary, micropapillary and solid. The complex gene interactions and anticancer immune response of these types are not well known. The aim of this study was to reveal the survival rates, genetic alterations and immune activities of the five histological types and provide treatment strategies. This study reviewed the histological findings of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and classified them into five types. We performed gene set enrichment analysis (GSEA) and survival analysis according to the different types. We found six oncogenic gene sets that were higher in lung adenocarcinoma than in normal tissues. In the survival analysis of each type, the acinar type had a favorable prognosis, and the solid subtype had an unfavorable prognosis; however, the survival differences between the other types were not significant. Our study focused on the solid type, which had the poorest prognosis. The solid type was related to adaptive immune resistance associated with elevated CD8 T cells and high CD274 (encoding PD-L1) expression. In the pathway analyses, the solid type was significantly related to high vascular endothelial growth factor (VEGF)-A expression, reflecting tumor angiogenesis. Non-necrosis/low immune response affected by high VEGF-A was associated with worse prognosis. The solid type associated with high VEGF-A expression may contribute to the development of therapeutic strategies for lung adenocarcinoma.

scholarly journals Motional dynamics of single Patched1 molecules in cilia are controlled by Hedgehog and cholesterol

2019 ◽  
Vol 116 (12) ◽  
pp. 5550-5557 ◽  
Author(s):  
Lucien E. Weiss ◽  
Ljiljana Milenkovic ◽  
Joshua Yoon ◽  
Tim Stearns ◽  
W. E. Moerner
Keyword(s):  
Single Molecule ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Transmembrane Protein ◽  
Cellular Level ◽  
Live Cells ◽  
Cholesterol Depletion ◽  
Motional Dynamics ◽  
Directional Transport ◽  
Bulk Behavior

The Hedgehog-signaling pathway is an important target in cancer research and regenerative medicine; yet, on the cellular level, many steps are still poorly understood. Extensive studies of the bulk behavior of the key proteins in the pathway established that during signal transduction they dynamically localize in primary cilia, antenna-like solitary organelles present on most cells. The secreted Hedgehog ligand Sonic Hedgehog (SHH) binds to its receptor Patched1 (PTCH1) in primary cilia, causing its inactivation and delocalization from cilia. At the same time, the transmembrane protein Smoothened (SMO) is released of its inhibition by PTCH1 and accumulates in cilia. We used advanced, single molecule-based microscopy to investigate these processes in live cells. As previously observed for SMO, PTCH1 molecules in cilia predominantly move by diffusion and less frequently by directional transport, and spend a fraction of time confined. After treatment with SHH we observed two major changes in the motional dynamics of PTCH1 in cilia. First, PTCH1 molecules spend more time as confined, and less time freely diffusing. This result could be mimicked by a depletion of cholesterol from cells. Second, after treatment with SHH, but not after cholesterol depletion, the molecules that remain in the diffusive state showed a significant increase in the diffusion coefficient. Therefore, PTCH1 inactivation by SHH changes the diffusive motion of PTCH1, possibly by modifying the membrane microenvironment in which PTCH1 resides.

scholarly journals Genetic Alterations in Patients With Esophageal Cancer With Short- and Long-Term Survival Rates After Curative Esophagectomy

1997 ◽  
Vol 226 (2) ◽  
pp. 162-168 ◽  
Author(s):  
Yutaka Shimada ◽  
Masayuki Imamura ◽  
Ichio Shibagaki ◽  
Hisashi Tanaka ◽  
Tokiharu Miyahara ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Survival Rates ◽  
Genetic Alterations ◽  
Term Survival ◽  
Long Term Survival ◽  
Short And Long Term ◽  
Curative Esophagectomy

scholarly journals Subperiosteal Anchorage in Orthodontics: A Narrative Review

2021 ◽  
Vol 11 (18) ◽  
pp. 8376
Author(s):  
Marco Serafin ◽  
Cinzia Maspero ◽  
Salvatore Bocchieri ◽  
Rosamaria Fastuca ◽  
Alberto Caprioglio
Keyword(s):  
Clinical Studies ◽  
Survival Rates ◽  
Biomechanical Properties ◽  
Previous Literature ◽  
Inclusion Criteria ◽  
Orthodontic Anchorage ◽  
Clinical Procedure ◽  
Advantages And Disadvantages ◽  
Current Review ◽  
Starting Point

Orthodontic anchorage is a necessity for every treatment and must be carefully evaluated by the orthodontist. It is defined as the resistance to unwanted dental movement of a tooth or a number of teeth by using different techniques. The purpose of the present paper is to highlight the subperiosteal anchorage applied to orthodontics; this technique has been debated in the literature and the purpose here is to summarize the fields of application. During the first check of previous literature 548 results were found, which have been reduced to 19 selected papers after application of the inclusion criteria and the elimination of duplicates. Multiple electronic databases were searched from 1 January 1995 to 31 December 2020 in order to identify papers eligible for current review. The data obtained by this review underlined the versatility of onplants used as absolute anchorage during orthodontic treatments, the advantages and disadvantages, the biomechanical properties and survival rates, and the clinical procedure. Further clinical studies and research are required to explore other kinds of application and to state specific guidelines; however, this study represents an update and a starting point for clinicians who want to use these devices and for further improvement of the technique.

scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

scholarly journals aPKC drives cilia-independent Hedgehog signaling to maintain basal cell carcinoma growth

2020 ◽  
Author(s):  
Tuyen T. L. Nguyen ◽  
Ung Seop Jeon ◽  
Vama Jhumkhawala ◽  
Kevin C. Tan ◽  
Vinay Kumar ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Usher Syndrome ◽  
Pathway Activity ◽  
Underlying Causes ◽  
Protein Kinase C Iota ◽  
Constitutively Active

AbstractPrimary cilia loss is a common feature of advanced cancers. While primary cilia are necessary to initiate Hedgehog (HH)-driven cancers, how HH pathway activity is maintained in advanced cancers devoid of primary cilia is unclear. Here, we find that HH-driven basal cell carcinoma (BCC) accumulate mutations in the Alström and Usher syndrome genes in advanced and SMO inhibitorresistant tumors. Loss of Alström and Usher syndrome gene expression, which are common underlying causes of deafness and blindness, suppresses ciliogenesis and HH signaling. Atypical protein kinase C iota/lambda (aPKC) is a GLI1 kinase with higher expression in advanced BCCs and we show that a constitutively active isoform drives HH pathway activity and mutually antagonizes primary cilia. Overexpression of the constitutively active aPKC variant can maintain HH pathway activity in the absence of primary cilia and can drive resistance to the SMO antagonist vismodegib regardless of cilia status. Finally, superficial BCCs display less primary cilia and higher aPKC expression, which is inversely correlated in nodular BCC subtypes. Our results suggest aPKC may serve as a biomarker for SMO inhibitor sensitivity and a target for clinical application.

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