Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes
Fibrosarcomas (FSA) are malignant mesenchymal tumors characterized by low chemo- and radiosensitivity. Development of novel treatment strategies for human adult FSA is hindered by the low incidence and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in do...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558624001453 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832557592078974976 |
|---|---|
| author | Mikiyo Weber Daniel Fuchs Amiskwia Pöschel Erin Beebe Zuzana Garajova Armin Jarosch Laura Kunz Witold Wolski Lennart Opitz Franco Guscetti Mirja C. Nolff Enni Markkanen |
| author_facet | Mikiyo Weber Daniel Fuchs Amiskwia Pöschel Erin Beebe Zuzana Garajova Armin Jarosch Laura Kunz Witold Wolski Lennart Opitz Franco Guscetti Mirja C. Nolff Enni Markkanen |
| author_sort | Mikiyo Weber |
| collection | DOAJ |
| description | Fibrosarcomas (FSA) are malignant mesenchymal tumors characterized by low chemo- and radiosensitivity. Development of novel treatment strategies for human adult FSA is hindered by the low incidence and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in domestic cats, hence potentially representing a clinically amenable model to assess novel therapies such as targeted imaging or theranostics. However, a lack of molecular characterization of FSA and adjacent normal tissue (NT) in both species hinders identification of tumor-specific targets and undermines the translational potential of feline FSA. Combining laser-capture microdissection, RNAsequencing and liquid chromatography-tandem mass spectrometry, we perform comprehensive profiling of 30 feline FSA and matched skeletal muscle, adipose and connective tissue. Clear inter-tissue differences allow identification of significantly upregulated and tumor-exclusive features that represent potential targets for diagnostic and therapeutic approaches. While feline FSA are characterized by hyperactive EIF2, TP53 and MYC signaling, immune-related and neuronal pathways emerge as modulators of tumor aggressiveness and immunosuppression. A high degree of molecular similarity with canine and adult FSA allows identification of tumor targets that are conserved across species. Significant enrichment in DNA repair pathways in feline FSA correlate with aggressive clinical behavior in human soft-tissue sarcoma. Finally, we leverage the molecular profiles to identify vulnerabilities, including sensitivity to ATR and PARP inhibition as potential treatment for feline FSA. In conclusion, this detailed landscape provides a rich resource to identify target candidates and therapeutic vulnerabilities within and across species and supports feline FSA as relevant models for the human disease. |
| format | Article |
| id | doaj-art-a52098bb23e64b259a25e3fcb996b584 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-a52098bb23e64b259a25e3fcb996b5842025-02-03T04:16:33ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-02-0160101104Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypesMikiyo Weber0Daniel Fuchs1Amiskwia Pöschel2Erin Beebe3Zuzana Garajova4Armin Jarosch5Laura Kunz6Witold Wolski7Lennart Opitz8Franco Guscetti9Mirja C. Nolff10Enni Markkanen11Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, SwitzerlandInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, SwitzerlandInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, SwitzerlandInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, SwitzerlandInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, SwitzerlandInstitute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, GermanyFunctional Genomics Center Zürich, ETH Zürich/University of Zurich, 8057 Zürich, SwitzerlandFunctional Genomics Center Zürich, ETH Zürich/University of Zurich, 8057 Zürich, SwitzerlandFunctional Genomics Center Zürich, ETH Zürich/University of Zurich, 8057 Zürich, SwitzerlandInstitute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, SwitzerlandClinic for Small Animal Surgery, Vetsuisse Faculty, University Animal Hospital, University of Zurich, Zurich, Switzerland; Corresponding author.Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zürich, Switzerland; Corresponding author.Fibrosarcomas (FSA) are malignant mesenchymal tumors characterized by low chemo- and radiosensitivity. Development of novel treatment strategies for human adult FSA is hindered by the low incidence and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in domestic cats, hence potentially representing a clinically amenable model to assess novel therapies such as targeted imaging or theranostics. However, a lack of molecular characterization of FSA and adjacent normal tissue (NT) in both species hinders identification of tumor-specific targets and undermines the translational potential of feline FSA. Combining laser-capture microdissection, RNAsequencing and liquid chromatography-tandem mass spectrometry, we perform comprehensive profiling of 30 feline FSA and matched skeletal muscle, adipose and connective tissue. Clear inter-tissue differences allow identification of significantly upregulated and tumor-exclusive features that represent potential targets for diagnostic and therapeutic approaches. While feline FSA are characterized by hyperactive EIF2, TP53 and MYC signaling, immune-related and neuronal pathways emerge as modulators of tumor aggressiveness and immunosuppression. A high degree of molecular similarity with canine and adult FSA allows identification of tumor targets that are conserved across species. Significant enrichment in DNA repair pathways in feline FSA correlate with aggressive clinical behavior in human soft-tissue sarcoma. Finally, we leverage the molecular profiles to identify vulnerabilities, including sensitivity to ATR and PARP inhibition as potential treatment for feline FSA. In conclusion, this detailed landscape provides a rich resource to identify target candidates and therapeutic vulnerabilities within and across species and supports feline FSA as relevant models for the human disease.http://www.sciencedirect.com/science/article/pii/S1476558624001453Soft-tissue sarcomaComparative oncologyDisease modelTumor targetingLaser-capture microdissectionRNAsequencing |
| spellingShingle | Mikiyo Weber Daniel Fuchs Amiskwia Pöschel Erin Beebe Zuzana Garajova Armin Jarosch Laura Kunz Witold Wolski Lennart Opitz Franco Guscetti Mirja C. Nolff Enni Markkanen Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes Neoplasia: An International Journal for Oncology Research Soft-tissue sarcoma Comparative oncology Disease model Tumor targeting Laser-capture microdissection RNAsequencing |
| title | Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes |
| title_full | Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes |
| title_fullStr | Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes |
| title_full_unstemmed | Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes |
| title_short | Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes |
| title_sort | transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes |
| topic | Soft-tissue sarcoma Comparative oncology Disease model Tumor targeting Laser-capture microdissection RNAsequencing |
| url | http://www.sciencedirect.com/science/article/pii/S1476558624001453 |
| work_keys_str_mv | AT mikiyoweber transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT danielfuchs transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT amiskwiaposchel transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT erinbeebe transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT zuzanagarajova transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT arminjarosch transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT laurakunz transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT witoldwolski transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT lennartopitz transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT francoguscetti transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT mirjacnolff transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes AT ennimarkkanen transcriptomicandproteomicprofilingidentifiesfelinefibrosarcomaasclinicallyamenablemodelforaggressivesarcomasubtypes |