scholarly journals CNA Profiling of Single CTCs in Locally Advanced Esophageal Cancer Patients during Therapy Highlights Unexplored Molecular Pathways

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6369
Author(s):  
Giulia Gallerani ◽  
Tania Rossi ◽  
Martina Valgiusti ◽  
Davide Angeli ◽  
Pietro Fici ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Immune System ◽  
Innate Immune System ◽  
Copy Number ◽  
Locally Advanced ◽  
Epigenetic Modifications ◽  
Innate Immune ◽  
Genomic Imbalance ◽  
Single Ctcs ◽  
Time Point

Background: Here, we monitored the evolution of CTCs spread in 11 patients affected by locally advanced EC who were undergoing therapy. Methods: In this perspective study, we designed multiple blood biopsies from individual patients: before and after neoadjuvant chemo-radio therapy and after surgery. We developed a multi-target array, named Grab-all assay, to estimate CTCs for their epithelial (EpCAM/E-Cadherin/Cytokeratins) and mesenchymal/stem (N-Cadherin/CD44v6/ABCG2) phenotypes. Identified CTCs were isolated as single cells by DEPArray, subjected to whole genome amplification, and copy number aberration (CNA) profiles were determined. Through bioinformatic analysis, we assessed the genomic imbalance of single CTCs, investigated specific focal copy number changes previously reported in EC and aberrant pathways using enrichment analysis. Results: Longitudinal monitoring allowed the identification of CTCs in at least one time-point per patient. Through single cell CNA analysis, we revealed that CTCs showed significantly dynamic genomic imbalance during treatment. Individual CTCs from relapsed patients displayed a higher degree of genomic imbalance relative to disease-free patients’ groups. Genomic aberrations previously reported in EC occurred mostly in post-neoadjuvant therapy CTCs. In-depth analysis showed that networks enrichment in all time-point CTCs were inherent to innate immune system. Transcription/gene regulation, post-transcriptional and epigenetic modifications were uniquely affected in CTCs of relapsed patients. Conclusions: Our data add clues to the comprehension of the role of CTCs in EC aggressiveness: chromosomal aberrations on genes related to innate immune system behave as relevant to the onset of CTC-status, whilst pathways of transcription/gene regulation, post-transcriptional and epigenetic modifications seem linked to patients’ outcome.

scholarly journals CNA profiling of single CTCs in locally advanced esophageal cancer patients during therapy highlights unexplored molecular pathways.

2021 ◽  
Author(s):  
Giulia Gallerani ◽  
Tania Rossi ◽  
Martina Valgiusti ◽  
Davide Angeli ◽  
Pietro Fici ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Gene Regulation ◽  
Immune System ◽  
Innate Immune System ◽  
Locally Advanced ◽  
Epigenetic Modifications ◽  
Innate Immune ◽  
Advanced Esophageal Cancer ◽  
Locally Advanced Esophageal Cancer

Abstract Locally advanced esophageal cancer (EC) is an aggressive disease with a dismal prognosis. The role of circulating tumor cells (CTC) in the EC metastatic process is still an unaddressed question. Here we monitored the evolution of CTCs spread in 11 patients affected by locally advanced EC who were undergoing neoadjuvant chemo-radio therapy followed by surgery. We developed an ad hoc assay named ‘Grab-all’ assay using DEPArray system. Longitudinal monitoring allowed the identification of CTCs expressing epithelial, mesenchymal or mixed phenotype markers, in at least one time-point per patient. Through single cell copy number aberration (CNA) analysis, we revealed that individual CTCs from relapsed patients displayed higher degree of genomic imbalance compared to disease-free patients' ones. Post-neoadjuvant therapy CTCs show genomic aberrations previously reported in EC, namely 23/23 amplifications and 13/19 deletions. Notably the phenomenon was not restricted to the group of relapsed patients. In-depth analysis showed that networks enrichment in all time-points CTCs were inherent to innate immune system. At variance, transcription/gene regulation, post-transcriptional and epigenetic modifications were uniquely affected in CTCs of relapsed patients. Collectively, our data add clues to the comprehension of the role of CTCs in EC aggressiveness: chromosomal aberrations on genes related to innate immune system behave as relevant to the onset of CTC-status, whilst pathways of transcription / gene regulation, post-transcriptional and epigenetic modifications seem linked to patients’ outcome.

scholarly journals Comparative genomics reveals the origins and diversity of arthropod immune systems

2014 ◽  
Author(s):  
William J Palmer ◽  
Francis M Jiggins
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Copy Number ◽  
Innate Immune ◽  
Signalling Pathway ◽  
Immune Systems ◽  
Number Variation ◽  
Pathogen Recognition Receptors ◽  
Cellular Immune ◽  
High Diversity

While the innate immune system of insects is well-studied, comparatively little is known about how other arthropods defend themselves against infection. We have characterised key immune components in the genomes of five chelicerates, a myriapod and a crustacean. We found clear traces of an ancient origin of innate immunity, with some arthropods having Tolllike receptors and C3-complement factors that are more closely related in sequence or structure to vertebrates than other arthropods. Across the arthropods some components of the immune system, like the Toll signalling pathway, are highly conserved. However, there is also remarkable diversity. The chelicerates apparently lack the Imd signalling pathway and BGRPs–a key class of pathogen recognition receptors. Many genes have large copy number variation across species, and this may sometimes be accompanied by changes in function. For example, peptidoglycan recognition proteins (PGRPs) have frequently lost their catalytic activity and switch between secreted and intracellular forms. There has been extensive duplication of the cellular immune receptor Dscam in several species, which may be an alternative way to generate the high diversity that produced by alternative splicing in insects. Our results provide a detailed analysis of the immune systems of several important groups of animals and lay the foundations for functional work on these groups.

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