Background
DNM2 deregulation in cancers
Type of cancer | DNM2 defect | Phenotypic association | References |
---|---|---|---|
Acute Lymphoblastic leukemia (adult and children) | Somatic Mutations | • High risk of treatment failure • Poor prognosis (adult) | |
Acute Lymphoblastic leukemia | Overexpression | • Cell proliferation • Poor prognosis | [31] |
Chronic myeloid leukemia | Overexpression | [32] | |
Ovarian | Overexpression | [33] | |
Bladder | Overexpression | • Correlated with grade progression | [34] |
Papillary Thyroid cancer | Overexpression | • Poor prognosis | [35] |
Prostate | Overexpression | • Aggressiveness • Mortality | |
Cervical | Overexpression | • Biomarker in grading neoplasia | |
Breast | Overexpression | • Relapse to chemotherapy in triple negative breast cancer • Cytoplasmic DNM2 in invasive ductal carcinoma • Plasma membrane DNM2 ➔ aggressiveness • Nuclear DNM2 staining correlated with tumor stages | |
Pancreas | Overexpression | • Cell migration and invasion • Lower man survival times | [42] |
Mechanisms responsible for DNM2 overexpression in cancers
Involvement of DNM2 dysfunction in cancer pathophysiology
Migration, invasion and metastasis
Cell proliferation and survival
Therapeutic developments
Type of cancer | Animal model | Approach for DNM2 reduction | Read out | Reference |
---|---|---|---|---|
Prostate | Implantation of tumor cells (PC3, LNCaP, and C4-2) in prostate of male SCID mice | Stable expression of DNM2-siRNA or scrambled-siRNA in injected cells | 9 weeks after cell injection: • Decrease in tumor weight • Reduction of number of lymph node metastases (for the PC3 cells able to induce metastases) | [36] |
Prostate | Subcutaneous injection of PC3 cells in athymic mice | Pharmacological inhibitor (DBHA). Intratumoral injection in tumors of 7–13 mm | • Reduction of the tumor volume at day 4 and day 8 after injection (vs vehicle injected tumors) • No apparent toxic effect at the necropsy (day 8) | [89] |
Pancreas | Implantation of tumor cells overexpressing DNM2 or phospho-deficient DNM2 (PxPC-3) in pancreas of nude mice | Stable expression of WT DNM2-GFP or phospho-deficient DNM2-GFP in injected cells | 2 weeks after cell injection: • Comparable size of primary tumor • Expression of the phospho-deficient mutant limits the distal dissemination of tumor cells from the injection area (vs WT DNM2-expressing cells) 8 weeks after cell injection: • Similar volume of the primary pancreas tumors • Large tumors in the body cavity • Expression of the mutant DNM2 decrease the number of large intestinal tumors vs WT DNM2-expressing cells • No liver tumors after injection of cells expressing the mutant (which occurs in 3 of 18 mice injected with cells overexpressing WT DNM2) | [42] |
Breast | Injection of tumor cells expressing inducible DNM2 shRNA (MDA-MB-231-BR3) into mammary fat pads of nude mice | Doxycycline-inducible shRNA against DNM2 and control shRNA in injected cells | • No decrease in tumor volume alone • Improvement of the tumor volume reduction induced by chemotherapy by cyclophosphamide | [41] |
Glioblastoma | Injection of tumor cells (LN444/PDGF-A) into the brain of mice | DNM2-siRNA or control-siRNA in injected cells | 8 weeks after cell injection: • Suppression of the PDGFRα–stimulated glioma growth (tumor volume) and invasion (number of prodruded fingers from tumors) • Decrease in tumor cell proliferation • Increase in cell apoptosis | [60] |
Glioblastoma | Injection of tumor cells (GSC#035 with stable expression of luciferase) into the brain of nude mice | Continuous release of a DNM2 inhibitor (CyDyn 4–36) for 14 days by subcutaneous osmotic minipumps once tumors were established | Luciferase in vivo imaging after 1, 4, 8, 11 and 14 days of treatment: • Reduction of tumor volume statistically significant from 11 days of treatment (vs vehicle treated mice) | [82] |
Leukemia | 6-week-old Lmo2Tg mice | IP injection twice daily for 5 days on 2 consecutive weeks of a DNM2 inhibitor (Dynole 34–2) | After 2 weeks of treatment: • Reduction in the number of DN3a thymocytes • Decrease in pre-LSC frequency • Progressive exhaustion of pre-LSCs In non-tumour-bearing control mice: no detrimental effect of treatment on differentiated cells in the thymus and the bone marrow or the number of phenotypic bone marrow stem and progenitor cells | [90] |
Leukemia | Injection of immature (ETP12) and mature (ALL8) T-ALL cell lines in mice | IP injection twice daily for 5 days on 2 consecutive weeks of a DNM2 inhibitor (Dynole 34–2). Treatment started when the average proportion of leukemic cells in the peripheral blood reached 1% | • Increased survival of treated mice 24 h after the last administration: • Reduction in leukemic cells in the peripheral blood, bone marrow and spleen • Inhibition of the abnormally activated IL-7 and NOTCH1 signaling pathways in leukemic cells | [90] |
Leukemia | Injection of AML cell lines AML01-307 and AML18) in immunodeficient mice | IP injection twice daily for 5 days on 2 consecutive weeks of a DNM2 inhibitor (Dynole 34–2) | • Delayed onset of the disease • Increased survival of treated mice 24 h after the last administration: • Inhibition of IL-3, GM-CSF and SCF signaling pathways in leukemic cells • Less patient-derived AML cells in bone marrow and spleen of treated mice | [90] |