Protocadherins at the Crossroad of Signaling Pathways

Pancho, Anna; Aerts, Tania; Mitsogiannis, Manuela D.; Seuntjens, Eve

doi:10.3389/fnmol.2020.00117

Cited by 110 publications

(89 citation statements)

References 301 publications

(504 reference statements)

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“…The cluster n genes were enriched in the GO set “homophilic cell adhesion via plasma membrane adhesion molecules”. Among them was the protocadherin cluster Pcdhb [ 32 ]. In contrast to cluster m , cluster n comprised genes expressed by secretory lineages such as Clca1 , Zg16 and NeuroG3 [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Drifts during Long-Term Intestinal Organoid Culture

Thalheim

Siebert

Quaas

et al. 2021

Cells

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Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and accessible to genetic engineering. Thus, they represent an optimal tool for studying the mechanisms of tissue maintenance and aging. Long-term expansion under standard growth conditions, however, is accompanied by changes in the growth pattern and kinetics. As a potential explanation of these alterations, epigenetic drifts in organoid culture have been suggested. Here, we studied histone tri-methylation at lysine 4 (H3K4me3) and 27 (H3K27me3) and transcriptome profiles of intestinal organoids derived from mismatch repair (MMR)-deficient and control mice and cultured for 3 and 20 weeks and compared them with data on their tissue of origin. We found that, besides the expected changes in short-term culture, the organoids showed profound changes in their epigenomes also during the long-term culture. The most prominent were epigenetic gene activation by H3K4me3 recruitment to previously unmodified genes and by H3K27me3 loss from originally bivalent genes. We showed that a long-term culture is linked to broad transcriptional changes that indicate an ongoing maturation and metabolic adaptation process. This process was disturbed in MMR-deficient mice, resulting in endoplasmic reticulum (ER) stress and Wnt activation. Our results can be explained in terms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed.

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Section: Resultsmentioning

confidence: 99%

Epigenetic Drifts during Long-Term Intestinal Organoid Culture

Thalheim

Siebert

Quaas

et al. 2021

Cells

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“…36 PCDHGC5 is a transmembrane protein belonging to the cadherin superfamily of intercellular adhesion and cellcell communication proteins, whose dysregulation has been associated with either cancer progression or suppression. 37 Ectopic expression of PCDHGC5 has been reported in astrocytomas, while its hypermethylation in a variety of other tumor types, including sarcomas. 38,39 As potential novel tumor antigens, GTF2I and PCDHGC5 expression and immunoreactivity was confirmed in ARMS cell lines and tumor specimens, while the autoantibody response was validated in a larger cohort of patients, including cases of ERMS.…”

Section: Discussionmentioning

confidence: 99%

Autoantibody profiling of alveolar rhabdomyosarcoma patients unveils tumor-associated antigens with diagnostic and prognostic significance

et al. 2021

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Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive subtype of childhood cancer for which efficacious treatments are needed. Immunotherapy represents a new therapeutic opportunity to pursue, but it requires the identification of worthwhile tumor antigens. Herein, we exploited the capacity of ARMS autoantibodies to recognize tumor self-antigens, probing human protein microarrays with plasma from ARMS patients and healthy subjects. We assessed the autoantibody response in ARMS, validated data with independent techniques, and estimated autoantibodies diagnostic and prognostic significance by receiver-operator characteristic curves (ROC), uni-and multivariate analysis. Of the 48 tumor antigens identified, General Transcription Factor II-I (GTF2i) and Protocadherin Gamma Subfamily C5 (PCDHGC5) were selected as candidate targets to validate tumor-restricted antigen expression and autoantibody reactivity through an independent technique and wider cohort of cases. GTF2i and PCDHGC5 overexpression was observed in tumor tissues compared to normal counterparts, and anti-GTF2i and -PCDHGC5 autoantibodies were found able to distinguish ARMS patients from healthy subjects as well as cases with different histology. Moreover, low levels of PCDHGC5 autoantibodies characterized patients with worse event-free survival and proved to be an independent negative prognostic factor. This approach provided the first comprehensive autoantibody profile of ARMS, gave novel insights into the immune response of this malignancy and paved the way toward novel potential antibody-based therapeutic applications suitable to improve the survival of ARMS patients.

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“…One possibility is that C-types form different within family extracellular interactions than alternate cPcdhs but our structural and biophysical data indicate that this is not the case and suggest the possibility that different intracellular interactions account for their specialized functions. The cytoplasmic domain plays an important role in the activation of Wnt, WAVE, and other signaling cascades (Chen et al, 2009;Fukuda et al, 2008;Keeler et al, 2015;Mah and Weiner, 2017;Onouchi et al, 2015;Pancho et al, 2020). 10…”

Section: Discussionmentioning

confidence: 99%

How clustered protocadherin binding specificity is tuned for neuronal self/non-self-recognition

Goodman

Katsamba

Rubinstein

et al. 2021

Preprint

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The stochastic expression of fewer than 60 clustered protocadherin (cPcdh) isoforms provides diverse identities to individual vertebrate neurons and a molecular basis for self/non-self-discrimination. cPcdhs form chains mediated by alternating cis and trans interactions between apposed membranes, which has been suggested to signal self-recognition. Such a mechanism requires that cPcdh cis dimers form promiscuously to generate diverse recognition units, and that trans interactions have precise specificity so that isoform mismatches terminate chain growth. However, the extent to which cPcdh interactions fulfill these requirements has not been definitively demonstrated. Here we report biophysical experiments showing that cPcdh cis interactions are promiscuous, but with preferences favoring formation of heterologous cis dimers. Trans-homophilic interactions are remarkably precise, with no evidence for heterophilic interactions between different isoforms. A new C-type cPcdh crystal structure and mutagenesis data help to explain these observations. Overall, the interaction characteristics we report for cPcdhs help explain their function in neuronal self/non-self-discrimination

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Protocadherins at the Crossroad of Signaling Pathways

Cited by 110 publications

References 301 publications

Epigenetic Drifts during Long-Term Intestinal Organoid Culture

Epigenetic Drifts during Long-Term Intestinal Organoid Culture

Autoantibody profiling of alveolar rhabdomyosarcoma patients unveils tumor-associated antigens with diagnostic and prognostic significance

How clustered protocadherin binding specificity is tuned for neuronal self/non-self-recognition

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