Marlee Rose Yancey

All Publications

• Targeting the mitotic kinase NEK2 enhances CDK4/6 inhibitor efficacy by potentiating genome instability. The Journal of biological chemistry Bobbitt, J. R., Cuellar-Vite, L., Weber-Bonk, K. L., Yancey, M. R., Majmudar, P. R., Keri, R. A. 2025; 301 (2): 108196

  Abstract

  Selective inhibitors that target cyclin-dependent kinases 4 and 6 (CDK4/6i) are approved by the U.S. Food and Drug Administration (FDA) for treatment of a subset of breast cancers and are being evaluated in numerous clinical trials for other cancers. Despite this advance, a subset of tumors are intrinsically resistant to these drugs and acquired resistance is nearly inevitable. Recent mechanistic evidence suggests that in addition to stalling the cell cycle, the antitumor effects of CDK4/6i involve the induction of chromosomal instability (CIN). Here, we exploit this mechanism by combining CDK4/6i with other instability-promoting agents to induce maladaptive CIN and irreversible cell fates. Specifically, dual targeting of CDK4/6 and the mitotic kinase NEK2 in vitro drives centrosome amplification and the accumulation of CIN that induces catastrophic mitoses, cell cycle exit, and cell death. Dual targeting also induces CIN in vivo and significantly decreases mouse tumor volume to a greater extent than either drug alone, without inducing overt toxicity. Importantly, we provide evidence that breast cancer cells are selectively dependent on NEK2, but nontransformed cells are not, in contrast with other mitotic kinases that are commonly essential in all cell types. These findings implicate NEK2 as a potential therapeutic target for breast cancer that could circumvent the dose-limiting toxicities that are commonly observed when blocking other mitotic kinases. Moreover, these data suggest that NEK2 inhibitors could be used to sensitize tumors to FDA-approved CDK4/6i for the treatment of breast cancers, improving their efficacy and providing a foundation for expanding the patient population that could benefit from CDK4/6i.

  View details for DOI 10.1016/j.jbc.2025.108196

  View details for PubMedID 39826695

  View details for PubMedCentralID PMC11849632

• Allogenic Vertebral Body Adherent Mesenchymal Stromal Cells Promote Muscle Recovery in Diabetic Mouse Model of Limb Ischemia. Annals of vascular surgery Madison, M. K., Doiron, T. S., Stashevsky, J., Zhang, N., Yancey, M., Gil, C. H., Aridi, H. D., Woods, E. J., Murphy, M. P., Miller, S. J. 2025; 110 (Pt A): 522-533

  Abstract

  Chronic limb-threatening ischemia (CLTI) carries a significant risk for amputation, especially in diabetic patients with poor options for revascularization. Phase I trials have demonstrated efficacy of allogeneic mesenchymal stromal cells (MSC) in treating diabetic CLTI. Vertebral bone-adherent mesenchymal stromal cells (vBA-MSC) are derived from vertebral bodies of deceased organ donors, which offer the distinct advantage of providing a 1,000x greater yield compared to that of living donor bone aspiration. This study describes the effects of intramuscular injection of allogenic vBA-MSC in promoting limb perfusion and muscle recovery in a diabetic CLTI mouse model.A CLTI mouse model was created through unilateral ligation of the femoral artery in male polygenic diabetic TALLYHO mice. The treated mice were injected with vBA-MSC into the gracilis muscle of the ischemic limb 7 days post ligation. Gastrocnemius or tibialis muscle was assessed postmortem for fibrosis by collagen staining, capillary density via immunohistochemistry, and mRNA by quantitative real-time polymerase chain reaction (PCR). Laser Doppler perfusion imaging and plantar flexion muscle testing (MT) were performed to quantify changes in limb perfusion and muscle function.Compared to vehicle (Veh) control, treated mice demonstrated indicators of muscle recovery, including decreased fibrosis, increased perfusion, muscle torque, and angiogenesis. PCR analysis of muscle obtained 7 and 30 days post vBA-MSC injection showed an upregulation in the expression of MyoD1 (P = 0.03) and MyH3 (P = 0.008) mRNA, representing muscle regeneration, vascular endothelial growth factor A (VEGF-A) (P = 0.002; P = 0.004) signifying angiogenesis as well as interleukin (IL-10) (P < 0.001), T regulatory cell marker Foxp3 (P = 0.04), and M2-biased macrophage marker Mrc1 (CD206) (P = 0.02).These findings indicate human allogeneic vBA-MSC ameliorate ischemic muscle damage and rescue muscle function. These results in a murine model will enable further studies to develop potential therapies for diabetic CLTI patients.

  View details for DOI 10.1016/j.avsg.2024.08.004

  View details for PubMedID 39343376