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Molecular Classification Based on the Gene Expression Profiles in Canine Histiocytic Sarcoma Cells
Hiroki Sakuma1, Hirotaka Tomiyasu1, Akiyoshi Tani1
1Laboratory of Veterinary Internal Medicine, Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Abstract:
The molecular abnormalities of canine histiocytic sarcoma (CHS) remain to be elucidated. We previously revealed that the sensitivities to dasatinib and trametinib were significantly various among CHS cell lines, indicating the differences in underlying molecular abnormalities. In the present study, we performed RNA sequencing analysis using 11 CHS cell lines to investigate molecular classifications based on the gene expression profiles (GEPs). The clustering analysis showed that CHS cell lines were divided into two distinct clusters. The comparisons of GEPs between the clusters extracted 675 differentially expressed genes (DEGs), and these DEGs were enriched with those related to the regulations of inflammatory responses. Among these DEGs, differences in the expressions of CCL3, CCL4, CCL7, CLEC7A, and TLR4 genes between the two groups were confirmed by RT-qPCR. Since no significant difference in the activation status of Akt and ERK pathways was observed between the two groups, the NF-κB pathway was focused on and its activation status was examined in the cell lines. As a result, cell lines belonging to one cluster showed nuclear translocation of the p65 protein together with increased release of CCL5 protein, which is a target molecule of the NF-κB pathway, in a cell culture supernatant. These results suggested that the molecular pathology of CHS cells might be divided into two categories depending on the activation status of the NF-κB pathway, and it is necessary to establish precision medicine for each molecular subtype of CHS.
Insights
Canine histiocytic sarcoma (CHS) molecular subtypes were identified using gene expression profiles. Two distinct clusters emerged, linked to NF-κB pathway activation, suggesting tailored precision medicine approaches for CHS treatment.
Area of Science:
- Veterinary Oncology
- Molecular Biology
- Canine Cancer Research
Background:
- Canine histiocytic sarcoma (CHS) molecular underpinnings are not fully understood.
- Previous studies showed variable drug sensitivities among CHS cell lines, hinting at diverse molecular abnormalities.
- Investigating these differences is crucial for developing effective treatments.
Purpose of the Study:
- To classify canine histiocytic sarcoma (CHS) cell lines based on gene expression profiles (GEPs).
- To identify molecular differences associated with distinct CHS subtypes.
- To explore potential therapeutic strategies based on identified molecular pathways.
Main Methods:
- RNA sequencing analysis of 11 CHS cell lines to generate GEPs.
- Clustering analysis to group cell lines based on GEPs.
- Differential gene expression analysis and RT-qPCR validation for key genes.
- Examination of NF-κB pathway activation status (p65 nuclear translocation, CCL5 release).
Main Results:
- CHS cell lines clustered into two distinct groups based on GEPs.
- 675 differentially expressed genes (DEGs) were identified, enriched in inflammatory response pathways.
- NF-κB pathway activation, indicated by p65 nuclear translocation and CCL5 release, distinguished one cluster.
- No significant difference in Akt or ERK pathway activation was observed between clusters.
Conclusions:
- Canine histiocytic sarcoma (CHS) exhibits molecular heterogeneity, potentially classifiable into two subtypes based on NF-κB pathway activation.
- These findings support the development of precision medicine tailored to specific molecular subtypes of CHS.
- Further research into these subtypes could lead to more targeted and effective therapeutic interventions.
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