Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target

  • Oncogenesis. 2025 Apr 11;14(1):9. doi: 10.1038/s41389-025-00554-5.
Oded Komemi  1  2 ,  Elina Orbuch  1  2 ,  Osnat Jarchowsky-Dolberg  2  3  4 ,  Yaron Shraga Brin  5 ,  Shelly Tartakover-Matalon  2  6 ,  Metsada Pasmanik-Chor  7 ,  Michael Lishner  1  2  4 ,  Liat Drucker  8  9
Affiliations
  • 1. Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
  • 2. Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
  • 3. Internal Medicine A, Meir Medical Center, Kfar Saba, Israel.
  • 4. Hematology Unit, Meir Medical Center, Kfar Saba, Israel.
  • 5. Orthopedics Department, Meir Medical Center, Kfar Saba, Israel.
  • 6. Autoimmunity Laboratory, Meir Medical Center, Kfar Saba, Israel.
  • 7. Bioinformatics Unit, G.S.W., Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
  • 8. Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel. [email protected].
  • 9. Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. [email protected].
PMID: 40216736 DOI: 10.1038/s41389-025-00554-5
Abstract

Bone-marrow mesenchymal stem cells (BM-MSCs) rely on glycolysis, yet their trafficked mitochondria benefit recipient cells' bioenergetics in regenerative and cancerous settings, most relevant to BM-resident multiple myeloma (MM) cells. Fission/fusion dynamics regulate mitochondria function. Proteomics demonstrates excessive mitochondrial processes in BM-MSCs from MM patients compared to normal donors (ND). Thus, we aimed to characterize BM-MSCs (ND, MM) mitochondrial fitness, bioenergetics and dynamics with a focus on therapeutics. MM-MSCs displayed compromised mitochondria evidenced by decreased mitochondrial membrane potential (ΔΨm) and elevated proton leak. This was accompanied by stimulation of stress-coping mechanisms: spare respiratory capacity (Src), mitochondrial fusion and UPRmt. Interfering with BM-MSCs mitochondrial dynamics equilibrium demonstrated their significance to bioenergetics and fitness according to the source. While ND-MSCs depended on fission, reducing MM-MSCs fusion attenuated glycolysis, OXPHOS and mtROS. Interestingly, optimization of mtROS levels is central to ΔΨm preservation in MM-MSCs only. MM-MSCs also demonstrated STAT3 activation, which regulates their OXPHOS and Src. Targeting MM-MSC' Src with Venetoclax diminished their pro-MM support and sensitized co-cultured MM cells to Bortezomib. Overall, MM-MSCs distinct mitochondrial bioenergetics are integral to their robustness. Repurposing Venetoclax as anti-SRC treatment in combination with conventional anti-MM drugs presents a potential selective way to target MM-MSCs conferred drug resistance.

Products