22 research outputs found

    A TORC2–Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers

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    The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus, a critical pathophysiologic event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency, and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers

    A TORC2–Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers

    No full text
    The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus a critical pathophysiological event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers

    Tumor-associated endothelial cells with cytogenetic abnormalities

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    Tumor angiogenesis is necessary for solid tumor progression and me-tastasis. Tumor blood vessels have been shown to differ from normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, although these endothelial cells are structurally and functionally abnormal. However, we hypothesized that given the phenotypic differences between tumor and normal blood vessels, there may be genotypic alterations as well. Mouse endothelial cells were isolated from two different human tumor xenografts, melanoma and liposarcoma, and from two normal endothelial cell counterparts, skin and adipose. Tumor-associated endothelial cells expressed typical endothelial cell markers, such as CD31. They had relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells were cytogenetically abnormal. Flu-orescence in situ hybridization (FISH) analysis showed that freshly iso-lated uncultured tumor endothelial cells were aneuploid and had abnor-mal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. Multicolor FISH indicated that the structural chro-mosomal aberrations in tumor endothelial cells were heterogeneous, indi-cating that the cytogenetic alterations were not clonal. There was no evidence of human tumor-derived chromosomal material in the mouse tumor endothelial cells. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid, had normal centrosomes, and remained cytogenetically stable in culture even up to 20 passages. FISH analysis of tumor sections also showed endothelial cell aneuploidy. We conclude that tumor endothelial cells can acquire cytogenetic abnormal-ities while in the tumor microenvironment

    Heat maps showing average response based on both raw data and disentanglement result within subtype to targeted therapeutics in Fig 8: (left) <b>HER2+</b>/<b>wild type</b>, (right) <b>HER2+</b>/ <b>PI3K mutant</b>.

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    <p>Each representation consists of average responses of raw RPPA, low-rank component and sparse component. Each row represents targeted therapeutics alone and in combination (<b>LAP, AKTi, both</b>). (A) In the <b>PI3K</b> mutation with applying both inhibitors, full inhibition of <b>pS6RP</b> is observed (B) the main difference between wild-type and <b>PI3K</b> mutant is the response of <b>pS6RP</b> and <b>p70S6K</b>.</p
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