Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion

Saito, Yasuhiro; Desai, Ridhdhi; Muthuswamy, Senthil K.

doi:10.1016/j.bbcan.2017.12.001

Cited by 45 publications

(44 citation statements)

References 193 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell polarity proteins can regulate molecular segregation processes within the subcellular space to make a cell more fit to perform certain biologic functions, such as proliferation, apoptosis, stress adaptation, stemness, and organelle biology (40). Cell polarity proteins are frequently targeted by different viruses, which affect not only host cell polarity but also many other cellular processes (39).…”

Section: Discussionmentioning

confidence: 99%

“…Because a virus tends to take over the cellular machinery of the host cell, of which polarity proteins are vital elements, one can speculate that the targeting of polarity proteins by the virus may bias cellular fitness as a crucial step toward making the subcellular environment more apt for its own replication, modifying signaling pathways and cellular and tissue homeostasis (39,40). The recent description of targeting of polarity proteins by viruses in additional immune cells, including APCs, (26) led us to hypothesize that modification of the cellular fitness landscape may occur as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.…”

Section: Viral Targeting Of Pdz Proteins In the Immune Systemmentioning

confidence: 99%

See 1 more Smart Citation

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Gutiérrez‐González¹,

Santos‐Mendoza

2019

FASEB j.

View full text Add to dashboard Cite

PDZ proteins are highly conserved through evolution; the principal function of this large family of proteins is to assemble protein complexes that are involved in many cellular processes, such as cell‐cell junctions, cell polarity, recycling, or trafficking. Many PDZ proteins that have been identified as targets of viral pathogens by promoting viral replication and spread are also involved in epithelial cell polarity. Here, we briefly review the PDZ polarity proteins in cells of the immune system to subsequently focus on our hypothesis that the viral PDZ‐dependent targeting of PDZ polarity proteins in these cells may alter the cellular fitness of the host to favor that of the virus; we further hypothesize that this modification of the cellular fitness landscape occurs as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.—Gutiérrez‐González, L. H., Santos‐Mendoza, T. Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism. FASEB J. 33, 10607–10617 (2019). http://www.fasebj.org

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Viral Targeting Of Pdz Proteins In the Immune Systemmentioning

confidence: 99%

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Gutiérrez‐González¹,

Santos‐Mendoza

2019

FASEB j.

View full text Add to dashboard Cite

show abstract

“…We used an informed approach to identify genes required for border cell migration that may have a role in GBM. In particular, we focused on the highly conserved PDZ-domain encoding genes, many of which have known or suspected roles in human tumorigenesis and cancer cell invasion 44,62,63 . Of these PDZ genes, plus related genes such as small GTPases with validated functions in border cells 30 , we identified a number of conserved genes whose elevated expression correlated with decreased GBM patient survival.…”

Section: Discussionmentioning

confidence: 99%

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Volovetz

Berezovsky

Alban

et al. 2019

Preprint

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development.Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs. RAP1A

show abstract

“…These competition mechanisms which eliminate abnormal cells, are essential to prevent tumor development and such a mechanism may be at play in the case of abnormal VANGL-polarized cells. Vang Gogh-like proteins are upregulated in many types of aggressive cancers and this upregulation is associated with poor patient prognosis in breast cancer 69–71 .…”

Section: Discussionmentioning

confidence: 99%

Apical restriction of the planar cell polarity component VANGL in pancreatic ducts is required to maintain epithelial integrity

Flasse

Yennek

Cortijo

et al. 2019

Preprint

View full text Add to dashboard Cite

15Cell polarity is essential for the architecture and function of numerous epithelial tissues. Here we show 16 how planar cell polarity (PCP), so far studied principally in flat epithelia, is deployed during the 17 morphogenesis of a tubular organ. Using the mammalian pancreas as a model, we report that 18 components of the core PCP pathway such as the transmembrane protein Van Gogh-like (VANGL), are 19 progressively apically-restricted. VANGL expression becomes asymmetrically localized at the apical 20 surface of ductal cells, revealing a planar polarization of the pancreatic duct. We further show that 21 restricting VANGL to these discrete sites of expression is crucial for epithelial integrity. Expansion of 22 expression on basolateral membranes of the progenitors leads to their death and extrusion from the 23 epithelium, as previously observed for perturbations of apico-basal polarity. Using organoids and in vivo 24 analyses, we show that cell elimination is induced by a decrease of Rock activity via Dishevelled. 25 2 group of six families of proteins is required to coordinate planar polarization between neighboring cells: 38 the transmembrane proteins Frizzled (vertebrate: FZD; fly: FZ), CELSR (CELSR; FMI) and Van Gogh-like 39 (VANGL; STBM/VANG) and the cytosolic-submembrane proteins Dishevelled (DVL; DSH), 40Inversin/Diversin (INV/ANKRD6; DGO), and Prickle (PK). The PCP signaling system employs intra-and inter-41 cellular feedback interactions between its core components to establish their characteristic asymmetric 42 cellular distributions. In the most comprehensively-characterized system, the Drosophila wing blade, the 43 FZ-DSH-DGO complex localizes to intercellular junctions facing the VANG-PK complex in the adjacent 44 cell. FMI, an atypical cadherin, localizes to both sides of the apical junction and bridges the FZ and VANG 45 complexes between neighboring cells. These intercellular interactions are counterbalanced 46 intracellularly by reciprocal inhibitory interactions between the two complexes 1,2 . 47While traditionally depicted in flat epithelia that require directional motion or an oriented structure, it is less 48 clear how these proteins are organized or function in complex epithelia forming tubular structures 3 . The 49 developing pancreas consists of a network of tubes lined by polarized progenitors, the apical membranes of 50 which line the duct lumen 4,5 . This network is dynamic and remodeled throughout development while the 51 pancreatic epithelium grows and progenitors commit to various specialized fates 6 . At embryonic day 52 E10.5, multipotent progenitors are organized around discrete micro-lumens 7,8 . By E12.5, these micro-53 lumens have fused to form a mesh of interconnected ducts. Distal "Tip" progenitors committed to an 54 exocrine fate are restricted to the periphery while the core of this plexus contains bipotent "Trunk" 55 progenitors that subsequently either remain in the epithelium to form mature duct cells or delaminate 56 to give rise to endocrine cells. By birth, the duc...

show abstract

Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion

Cited by 45 publications

References 193 publications

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Apical restriction of the planar cell polarity component VANGL in pancreatic ducts is required to maintain epithelial integrity

Contact Info

Product

Resources

About