Molecular pathogenesis and investigation of novel therapy for canine histiocytic sarcoma
Prognosis of dogs with histiocytic sarcoma is very poor. We reported that about 40% of dogs with this disease harbored mutations of TP53 gene (Asada et al., J. Vet. Med. Sci. 2017) We also reported the effects of the mutations on functions of TP53 genes (Asada et al., Am. J. Vet. Res. 2019), intratumor heterogeneity of this mutation (Asada et al., J. Vet. Med. Sci. 2019), and clinical significance of these mutations (Asada et al., Res. Vet. Sci. 2019).
Also, we have comprehensively examined molecular pathogenesis of canine histiocytic sarcoma using whole exome sequencing and transcriptome analysis by next generation sequencing.
In addition, we have tried to establish novel effective treatment for canine histiocytic sarcoma based on the results of our previous studies.
Molecular pathogenesis of bone marrow diseases in small animals
Bone marrow diseases are one of the important causes of cytopenias including anemia. Bone marrow diseases in small animals include tumors such as leukemia, dysplastic diseases, and immune-mediated diseases. Of these diseases, immune-mediated ones are frequently observed in dogs and cats. However, we think that "immune-mediated diseases" might have true pathogenesis rather than immunological aberrations based on the results of our recent studies.
Recently, we found bone marrow disorders that induced non-regenerative anemia frequently occurred in Miniature Dachshunds, and we revealed clinical features of such disorders in this breed (Tani et al., J Vet Med Sci 2020). Therefore, we have comprehensively investigated genomic and epigenomic aberrations and their associations with pathogenesis of bone marrow diseases in small animals.
Our final goal is to establish novel effective treatments for bone marrow diseases in small animals based on the novel concept of pathogenesis.
Role of exosomes in canine lymphoma cells
Recently, it has been revealed that interactions between tumor cells and surrounding microenvironment in tumor tissues play important roles in progression of tumors. We have focused on exosome, which is one of the extracellular vehicles, as a factor used in such interactions between tumor cells and microenvironment.
We revealed the profiles of molecules incuded in exosomes derived from canine lymphoma cells(Asada et al., PLoS One 2019). Based on these results, we have investigated the effects of exosomes derived from tumor cells on the functions of immune cells.
Our final goal is to establish novel effective treatments for canine lymphoma that target the interactions between tumor cells and microenvironments.
Elucidation of molecular mechanisms of chemotherapy resistance in canine lymphoma
Most of dogs with lymphoma respond to chemotherapy well at first; however, cure of this disease is challenging due to relapse and acquisition of chemotherapy resistance. We have conducted many studies for elucidation of the molecular mechanisms of chemotherapy resistance to overcome it (Tomiyasu et al., Vet. Sci. 2015 Review). However, we found that mechanisms of chemotherapy resistance in canine lymphoma cannot be explained by known molecules such as P-glycoprotein (P-gp).
Recently, we conducted the comprehensive comparisons of gene expression profiles between chemotherapy-sensitive and -resistant phases of dogs with lymphoma, and candidates of novel chemotherapy-resistant factors were identified (Suenaga et al., Vet. J. 2017). Now, we have investigated how these molecules can induce the chemotherapy resistance, and tried to establish the systems to predict the sensitivity for chemotherapy resistance prior to administration of drugs.
Elucidation of molecular mechanisms of chemotherapy resistance in feline lymphoma
Feline lymphoma also responds to chemotherapy well at first. However, relapse and acquisition of chemotherapy resistance are observed in most patients.
So far, there are few studies that examined the molecular mechanisms of chemotherapy resistance in feline lymphoma. We started to investigate the factors that contribute to acquisition of chemotherapy resistance by comparing comprehensive gene expression profiles between chemotherapy-sensitive and -resistant feline lymphoma patients.