Related Experiment Video

Updated: Jun 14, 2025

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
08:48

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation

Published on: June 30, 2015

8.2K

Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis

Islam E Elkholi, Amélie Robert, Camille Malouf

    Biorxiv : the Preprint Server for Biology
    |August 30, 2024
    PubMed

    Insights

    Targeting class III PI3K (Phosphoinositide 3-kinase) halts dormant breast cancer cell metastasis. This pathway is crucial for peripheral lysosomal positioning and mTORC1 hyperactivity in dormancy-prone cells, offering a potential therapeutic strategy.

    Area of Science:

    • Oncology
    • Cell Biology
    • Molecular Biology

    Background:

    • Metastatic relapse of breast cancer after primary tumor removal and dormancy presents a significant clinical challenge.
    • Identifying specific vulnerabilities in dormant cancer cells is crucial for preventing metastasis.

    Purpose of the Study:

    • To identify vulnerabilities in dormant breast cancer cells.
    • To investigate the role of class III PI3K (Phosphoinositide 3-kinase) in dormancy-prone breast cancer cells.

    Main Methods:

    • Genome-wide CRISPR screens were performed on two breast cancer cell lines (4T1 and 4T07) with differing dormancy properties.
    • Pharmacological inhibition of Pik3c3 was used to assess its effect on 4T07 cells.
    • The mechanism was validated in human breast cancer cell lines and a patient-derived xenograft model.

    Main Results:

    • Loss of Pik3c3 revealed a unique vulnerability in dormancy-prone 4T07 cells.
    • Dormancy-prone 4T07 cells showed higher mTORC1 activity due to lysosome-dependent peripheral signaling.
    • Inhibition of Pik3c3 counteracted this phenotype and reduced metastasis burden in the 4T07 model.
    • The observed mechanism was relevant in human breast cancer models.

    Conclusions:

    • Dormancy-prone breast cancer cells rely on class III PI3K for peripheral lysosomal positioning and mTORC1 hyperactivity.
    • Targeting this PI3K-dependent pathway may be a viable strategy to prevent metastasis initiated by dormant cancer cells.

    More Related Videos

    Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment11:13

    Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment

    Published on: June 9, 2023

    1.5K
    An In Vitro System to Study Tumor Dormancy and the Switch to Metastatic Growth09:14

    An In Vitro System to Study Tumor Dormancy and the Switch to Metastatic Growth

    Published on: August 11, 2011

    15.8K

    Related Concept Videos

    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
    The mTOR pathway or the...
    3.8K
    PI3K/mTOR/AKT Signaling Pathway01:22

    PI3K/mTOR/AKT Signaling Pathway

    The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
    3.4K
    Metastasis02:30

    Metastasis

    Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
    Epithelial-to-Mesenchymal Transition
    The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
    5.5K
    Interactions Between Signaling Pathways01:19

    Interactions Between Signaling Pathways

    Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
    Convergence and divergence, and cross-talk between signaling pathways
    Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
    6.2K
    The JAK-STAT Signaling Pathway01:20

    The JAK-STAT Signaling Pathway

    Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
    8.7K
    Inhibition of Cdk Activity02:34

    Inhibition of Cdk Activity

    The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
    4.7K