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| Status |
Public on Mar 22, 2022 |
| Title |
Elucidation of focal adhesion kinase as a modulator of migration and invasion and as a potential therapeutic target in chronic lymphocytic leukemia (RNA-Seq II) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibition of tumor cell migration. We compared the phenotypic and transcriptional changes induced in CLL cells using two distinct models designed to recapitulate the peripheral circulation, CLL cell migration across an endothelial barrier and the lymph node interaction between CLL cells and activated T cells. Initially, CLL cells were co-cultured with CD40L-expressing fibroblasts and exhibited an activated B-cell phenotype and their transcriptional signatures demonstrated the upregulation of pro-survival and anti-apoptotic genes and overrepresentation of the NF-κB signaling pathway. Using our dynamic circulating model we were able to study the transcriptomics and miRNomics associated with CLL migration. More than 3000 genes were altered when CLL cells underwent transendothelial migration, with overrepresentation of adhesion and cell migration gene sets. From this analysis an upregulation of the FAK signaling pathway was observed. Importantly, ptk2 (FAK) gene expression was significantly upregulated in migrating CLL cells (ptk2 Fold-change= 5.0). Here we demonstrate that TLR9 agonism increased levels of p-FAK (p<0.05) which could be prevented by pharmacological inhibition of FAK with defactinib (p<0.01). Furthermore, a reduction in CLL cell migration and invasion was observed when FAK was inhibited (p<0.05), supporting a role for FAK in both CLL migration and tissue invasion. Taken together, our data highlights the potential for combining FAK inhibition with current targeted therapies as a more effective treatment regime for CLL.
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| Overall design |
RNA-Seq CD40L expressing fibroblast co-culture with CLL cells
|
| Web link |
https://www.mdpi.com/2072-6694/14/7/1600/htm
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| |
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| Contributor(s) |
Burley TA, Hesketh A, Bucca G, Kennedy E, Ladikou EE, Towler B, Mitchell S, Smith CP, Fegan C, Johnston R, Pepper A, Pepper C |
| Citation(s) |
35326640, 35406371 |
| |
| Submission date |
Mar 11, 2022 |
| Last update date |
Aug 31, 2022 |
| Contact name |
Chris Pepper |
| E-mail(s) |
[email protected]
|
| Phone |
+ 44 (0)1273 678644
|
| Organization name |
University of Sussex
|
| Department |
Brighton and Sussex Medical School
|
| Street address |
Falmer
|
| City |
BRIGHTON |
| ZIP/Postal code |
BN1 9PX |
| Country |
United Kingdom |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE198456 |
Elucidation of focal adhesion kinase as a modulator of migration and invasion and as a potential therapeutic target in chronic lymphocytic leukemia |
|
| Relations |
| BioProject |
PRJNA815332 |
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