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Cited by 15Multiple Myeloma Research and TreatmentsPI3K/AKT/mTOR signaling in cancerMesenchymal stem cell research

Inhibiting PI3K–AKT–mTOR Signaling in Multiple Myeloma-Associated Mesenchymal Stem Cells Impedes the Proliferation of Multiple Myeloma Cells

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Heinemann, Luca, Möllers, Klara Maria, Ahmed, Helal Mohammed Mohammed, Wei, Lanying, Sun, Kaiyan, Nimmagadda, Subbaiah Chary, Frank, Daria, Baumann, Anja +5 more·2022·Frontiers in Oncology
DOI 10.3389/fonc.2022.874325PMC PMC9251191
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Abstract

The microenvironment of cancer cells is receiving increasing attention as an important factor influencing the progression and prognosis of tumor diseases. In multiple myeloma (MM), a hematological cancer of plasma cells, mesenchymal stem cells (MSCs) represent an integral part of the bone marrow niche and tumor microenvironment. It has been described that MM cells alter MSCs in a way that MM-associated MSCs promote the proliferation and survival of MM cells. Yet, our understanding of the molecular mechanisms governing the interaction between MM cells and MSCs and whether this can be targeted for therapeutic interventions is limited. To identify potential molecular targets, we examined MSCs by RNA sequencing and Western blot analysis. We report that MSCs from MM patients with active disease (MM-Act-MSCs) show a distinct gene expression profile as compared with MSCs from patients with other (non-) malignant diseases (CTR-MSCs). Of note, we detected a significant enrichment of the PI3K–AKT–mTOR hallmark gene set in MM-Act-MSCs and further confirmed the increased levels of related proteins in these MSCs. Pictilisib, a pan-PI3K inhibitor, selectively reduced the proliferation of MM-Act-MSCs as compared with CTR-MSCs. Furthermore, pictilisib treatment impaired the MM-promoting function of MM-Act-MSCs. Our data thus provide a deeper insight into the molecular signature and function of MSCs associated with MM and show that targeting PI3K–AKT–mTOR signaling in MSCs may represent an additional therapeutic pathway in the treatment of MM patients.

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  • Targeting the PI3K-AKT-mTOR signaling cascade within mesenchymal stromal cells using a pan-PI3K inhibitor (like pictilisib) selectively impedes the proliferation of multiple myeloma-associated mesenchymal stromal cells while diminishing their supportive role in promoting tumor progression.

    “Specifically targeting this intricate signaling cascade within MSCs using a pan-PI3K inhibitor (like pictilisib) has been shown to selectively impede the proliferation of MM-associated MSCs while simultaneously diminishing their supportive role in promoting tumor progression [267].”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [267]

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  • Mesenchymal stromal cells derived from multiple myeloma patients with active disease exhibit a distinct gene expression profile characterized by an evident overrepresentation of the PI3K-AKT-mTOR hallmark gene set.

    “Notably, MSCs derived from MM patients with active disease exhibit a distinct gene expression profile characterized by an evident overrepresentation of the PI3K-AKT-mTOR hallmark gene set.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [267]

  • The PI3K-AKT-mTOR signaling pathway is a crucial mediator in the dynamic interplay between multiple myeloma cells and mesenchymal stromal cells.

    “Some studies suggested that the PI3K-AKT-mTOR signaling pathway is a crucial mediator in the dynamic interplay between MM cells and MSCs.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [267]

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Cited by

Sorted by citations

Authors
Heinemann, L., Möllers, K. M., Ahmed, H. M. M., Wei, L., Sun, K., Nimmagadda, S. C., Frank, D., Baumann, A., Poos, A. M., Dugas, M., Varghese, J., Raab, M.-S., & Khandanpour, C.
Affiliations
  • University Hospital Münster (DE)
  • University of Münster (DE)
  • German Cancer Research Center (DE)
  • University Hospital Heidelberg (DE)
Corresponding author
Khandanpour, Cyrus
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2022-06-20
Volume
12
Pages
874325-874325
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2022.874325
PMC
PMC9251191
OpenAlex
W4283167247
Cited by
15
References
4
Citations by year
2026: 5 · 2025: 5 · 2024: 1 · 2023: 4
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • URN:NBN Resolver for Germany & Switzerland (German National Library) (submittedVersion, cc-by)
  • Universitäts- und Landesbibliothek Münster (cc-by)
Funders
  • Deutsche Forschungsgemeinschaft
  • Fundación Josep Carreras Contra la Leucemia
  • Deutsche Krebshilfe
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
multiple myeloma, mesenchymal stem cells, PI3K/AKT/mTOR pathway, pictilisib, PI3K inhibition, tumor microenvironment, bone marrow microenvironment, myeloma cell proliferation, therapeutic target

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