CDK5 Involvement in Cancer and in the Tumor Microenvironment

Farina, Floriana (2020). CDK5 Involvement in Cancer and in the Tumor Microenvironment. PhD thesis The Open University.



Part 1
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the CDK family, firstly discovered as a major player of neuronal development, bet several groups revealed additional roles of CDK5 especially in cancer. Indeed, CDK5 is reported to act as a tumor promoter in various types of solid tumors, but no reports indicated CDK5 involvement in hematopoietic malignancies development and progression.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin lymphoma. Despite a favourable therapeutic response to first-line chemo-immunotherapy, still 30–40% of patients are refractory, or relapse after this treatment. Thus, alternative strategies must be sought.

We demonstrated that CDK5 and its activator, cyclin-dependent kinase 5 activator 1 (CDK5R1 or p35), are overexpressed in DLBCL. Their role is mediated through the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and regulate proliferation and survival of DLBCL cells.

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression and are involved in cancer initiation and progression. We identify miR-26a as direct regulator of p35 expression and CDK5 activity. In addition, we show that miR-26a ectopic expression leads to a drastic reduction of DLBCL tumor progression both in vitro and in vivo.

In conclusion, these results demonstrate an important role for miR-26a and CDK5 together in the survival and growth of DLBCL cells, suggesting the existence of potential novel therapeutic targets for the treatment of DLBCL.

Part 2
Breast cancer is one of the most common cancers and the leading causes of death in women worldwide. It is complex tissues composed of neoplastic cells, surrounded by several stromal cell types that comprise the tumor microenvironment. Within the microenvironment, immune cells and especially Tumor-Associated Macrophages (TAMs) have been reported to regulate cancer progression and metastasis formation, and that a paracrine interaction between cancer cells and macrophages is required for invasion and intravasation in vivo. Until now, no previous work described CDK5 involvement in breast cancer-associated Macrophages.

Firstly, we revealed that CDK5 is not only expressed in the tumor mass of human breast cancer specimens, but it is also detectable in the tumor microenvironment. In particular, its expression was found in TAMs.

To dissect CDK5 involvement in TAMs, we measured its expression through in silico analysis and in vitro assays. We found that CDK5 is expressed in differentiated macrophages and it is downregulated after inflammatory stimuli. Through gain and loss-of-function experiments, we found that CDK5 inhibition is necessary for M1 polarization and M1 cytokines production. In addition, CDK5 silencing in vitro, induced a reduction in podosome formation.

To conclude, these data suggest p35/CDK5 involvement in cancer invasion and in the regulation of immune escape mechanisms. In addition, CDK5 expression in TAMs might be used as prognostic marker for the outcome evaluation of cancer patients. We aim to demonstrate that CDK5 inhibition might be a viable strategy to treat invasive breast cancer.

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