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PI3K-activated MSC proteomes inhibit mammary tumors via Hsp90ab1 and Myh9

Xun Sun1,2, Kexin Li1,2, Uma K Aryal3

  • 1Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China.

Molecular Therapy Oncolytics
|September 12, 2022
PubMed

Insights

This study shows activating PI3K in mesenchymal stem cells (MSCs) creates tumor-suppressing properties. YS49-treated MSCs effectively reduced breast cancer growth and spread, offering a new treatment avenue.

Area of Science:

  • Oncology
  • Stem Cell Biology
  • Molecular Medicine

Background:

  • Aggressive breast cancers, like triple-negative breast cancer, remain challenging to treat with current therapies.
  • Mesenchymal stem cells (MSCs) have immunomodulatory properties but their direct role in tumor suppression is complex.
  • Targeting key signaling pathways in MSCs may reprogram their function towards anti-tumorigenic effects.

Purpose of the Study:

  • To investigate the potential of activating PI3K/Akt signaling in human bone marrow-derived MSCs to induce tumor-suppressive capabilities.
  • To evaluate the efficacy of YS49-treated MSC-derived conditioned media (CM) in inhibiting breast cancer progression and metastasis.
  • To identify novel tumor-suppressing proteins involved in this MSC-mediated anti-cancer effect.

Main Methods:

  • Activation of PI3K/Akt pathway in MSCs using YS49, a specific activator.
  • Administration of MSC-derived CM to mouse models of mammary tumors.
  • Ex vivo assessment of CM's effect on human breast cancer tissues.
  • Proteomic analysis to identify key proteins in CM, including Hsp90ab1 and Myh9.

Main Results:

  • PI3K activation in MSCs led to the generation of tumor-suppressive proteomes, contrasting with tumor-promotive proteomes in PI3K-inactivated MSCs.
  • YS49-treated MSC-derived CM significantly decreased primary mammary tumor progression and lung metastasis in a mouse model.
  • Ex vivo assays showed YS49-treated MSC-derived CM reduced the size of various human breast cancer tissues.
  • Extracellular Hsp90ab1 and Myh9 were identified as key anti-tumorigenic proteins that also inhibited osteoclast maturation.

Conclusions:

  • Activation of PI3K signaling in MSCs can reprogram them to exhibit potent tumor-suppressive functions.
  • MSC-derived CM, particularly when enriched with Hsp90ab1 and Myh9, demonstrates significant anti-cancer activity against breast cancer.
  • This approach holds promise for developing novel cell-based therapies for breast cancer and preventing bone metastasis.
Keywords:
Hsp90ab1MSCMyh9PI3K/Aktbone metastasisbreast cancer

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