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Miller, Miles

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Miller

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Miles

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Miller, Miles
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Now showing 1 - 7 of 7
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    Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging
    (Nature Publishing Group, 2017) Cuccarese, Michael F.; Dubach, J. Matthew; Pfirschke, Christina; Engblom, Camilla; Garris, Christopher; Miller, Miles; Pittet, Mikael; Weissleder, Ralph
    Involvement of the immune system in tumour progression is at the forefront of cancer research. Analysis of the tumour immune microenvironment has yielded a wealth of information on tumour biology, and alterations in some immune subtypes, such as tumour-associated macrophages (TAM), can be strong prognostic indicators. Here, we use optical tissue clearing and a TAM-targeting injectable fluorescent nanoparticle (NP) to examine three-dimensional TAM composition, tumour-to-tumour heterogeneity, response to colony-stimulating factor 1 receptor (CSF-1R) blockade and nanoparticle-based drug delivery in murine pulmonary carcinoma. The method allows for rapid tumour volume assessment and spatial information on TAM infiltration at the cellular level in entire lungs. This method reveals that TAM density was heterogeneous across tumours in the same animal, overall TAM density is different among separate pulmonary tumour models, nanotherapeutic drug delivery correlated with TAM heterogeneity, and successful response to CSF-1R blockade is characterized by enhanced TAM penetration throughout and within tumours.
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    Profiling of metalloprotease activities in cerebrospinal fluids of patients with neoplastic meningitis
    (BioMed Central, 2017) Conrad, Catharina; Dorzweiler, Kristina; Miller, Miles; Lauffenburger, Douglas A.; Strik, Herwig; Bartsch, Jörg W.
    Background: Neoplastic invasion into leptomeninges and subarachnoid space, resulting in neoplastic meningitis (NM) is a fatal complication of advanced solid and hematological neoplasms. Identification of malignant involvement of the cerebrospinal fluid (CSF) early in the disease course has crucial prognostic and therapeutic implications, but remains challenging. As indicators of extracellular matrix (ECM) degradation and breakdown of the blood–brain-barrier, Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloproteases (ADAMs) are potential analytes for cerebral pathophysiology and metastatic dissemination of tumor cells into the CSF. Methods: We compared protease activities in CSF samples from patients with NM and control individuals using FRET-based metalloprotease substrates with distinct enzyme selectivity profiles in a real-time, multiplex approach termed “proteolytic activity matrix assay” (PrAMA). Protease activity dynamics can be tracked by fluorescence changes over time. By simultaneously monitoring a panel of 5 FRET-substrate cleavages, a proteolytic signature can be identified and analyzed to infer the activities of multiple specific proteases. Distinct patterns of substrate cleavage comparing disease vs. control samples allow rapid, reproducible and sensitive discrimination even in small volumes of CSF. Results: Individual substrate cleavage rates were linked to distinct proteases, and PrAMA computational inference implied increased activities of MMP-9, ADAM8 and ADAM17 (4–5-fold on average) in CSF samples from NM patients that were inhibitable by the metalloprotease inhibitor batimastat (BB-94). The activities of these proteases correlated with blood–brain barrier impairment. Notably, CSF cell counts were not found to directly reflect the protease activities observed in CSF samples from NM patients; this may explain the frequent clinical observation of negative cytology in NM patients. Conclusion: PrAMA analysis of CSF samples is a potential diagnostic method for sensitive detection of NM and may be suitable for the clinical routine. Electronic supplementary material The online version of this article (doi:10.1186/s12987-017-0070-5) contains supplementary material, which is available to authorized users.
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    Prediction of Anti-cancer Nanotherapy Efficacy by Imaging
    (Ivyspring International Publisher, 2017) Miller, Miles; Arlauckas, Sean; Weissleder, Ralph
    Anticancer nanotherapeutics have shown mixed results in clinical trials, raising the questions of whether imaging should be used to i) identify patients with a higher likelihood of nanoparticle accumulation, ii) assess nanotherapeutic efficacy before traditional measures show response, and iii) guide adjuvant treatments to enhance therapeutic nanoparticle (TNP) delivery. Here we review the use of a clinically approved MRI nanoparticle (ferumoxytol, FMX) to predict TNP delivery and efficacy. It is becoming increasingly apparent that nanoparticles used for imaging, despite clearly distinct physicochemical properties, often co-localize with TNP in tumors. This evidence offers the possibility of using FMX as a generic “companion diagnostic” nanoparticle for multiple TNP formulations, thus potentially allowing many of the complex regulatory and cost challenges of other approaches to be avoided.
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    Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor
    (Nature Publishing Group, 2014) Turetsky, Anna; Kim, Eunha; Kohler, Rainer; Miller, Miles; Weissleder, Ralph
    A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK-positive tumor-associated host cells.
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    MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis
    (The American Society for Cell Biology, 2016) Oudin, Madeleine J.; Miller, Miles; Klazen, Joelle A. Z.; Kosciuk, Tatsiana; Lussiez, Alisha; Hughes, Shannon K.; Tadros, Jenny; Bear, James E.; Lauffenburger, Douglas A.; Gertler, Frank B.
    Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis—the directional movement of cells to soluble cues—and haptotaxis—the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. MenaINV has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B and more recently in haptotaxis via interaction with integrin α5β1. Here we find that MenaINV-driven haptotaxis on fibronectin (FN) gradients requires intact signaling between α5β1 integrin and the epidermal growth factor receptor (EGFR), which is influenced by PTP1B. Furthermore, we show that MenaINV-driven haptotaxis and ECM reorganization both require the Rab-coupling protein RCP, which mediates α5β1 and EGFR recycling. Finally, MenaINV promotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyperinvasive phenotypes. Together our data demonstrate that MenaINV is a shared component of multiple prometastatic pathways that amplifies their combined effects, promoting synergistic cross-talk between RTKs and integrins.
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    Tumor associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
    (2015) Miller, Miles; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer; Iwamoto, Yoshiko; Yang, Katherine; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid; Weissleder, Ralph
    Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behavior. Model TNPs comprised of a fluorescent platinum(IV) pro-drug and a clinically-tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumor associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload, and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA damaging Pt payload gradually releases to neighboring tumor cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.
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    Modification of proteolytic activity matrix analysis (PrAMA) to measure ADAM10 and ADAM17 sheddase activities in cell and tissue lysates
    (Ivyspring International Publisher, 2017) Yoneyama, Toshie; Gorry, Michael; Miller, Miles; Gaither-Davis, Autumn; Lin, Yan; Moss, Marcia L.; Griffith, Linda G.; Lauffenburger, Douglas A.; Stabile, Laura P.; Herman, James G.; Vujanovic, Nikola L.
    Increases in expression of ADAM10 and ADAM17 genes and proteins have been evaluated, but not validated as cancer biomarkers. Specific enzyme activities better reflect enzyme cellular functions, and might be better biomarkers than enzyme genes or proteins. However, no high throughput assay is available to test this possibility. Recent studies have developed the high throughput real-time proteolytic activity matrix analysis (PrAMA) that integrates the enzymatic processing of multiple enzyme substrates with mathematical-modeling computation. The original PrAMA measures with significant accuracy the activities of individual metalloproteinases expressed on live cells. To make the biomarker assay usable in clinical practice, we modified PrAMA by testing enzymatic activities in cell and tissue lysates supplemented with broad-spectrum non-MP enzyme inhibitors, and by maximizing the assay specificity using systematic mathematical-modeling analyses. The modified PrAMA accurately measured the absence and decreases of ADAM10 sheddase activity (ADAM10sa) and ADAM17sa in ADAM10-/- and ADAM17-/- mouse embryonic fibroblasts (MEFs), and ADAM10- and ADAM17-siRNA transfected human cancer cells, respectively. It also measured the restoration and inhibition of ADAM10sa in ADAM10-cDNA-transfected ADAM10-/- MEFs and GI254023X-treated human cancer cell and tissue lysates, respectively. Additionally, the modified PrAMA simultaneously quantified with significant accuracy ADAM10sa and ADAM17sa in multiple human tumor specimens, and showed the essential characteristics of a robust high throughput multiplex assay that could be broadly used in biomarker studies. Selectively measuring specific enzyme activities, this new clinically applicable assay is potentially superior to the standard protein- and gene-expression assays that do not distinguish active and inactive enzyme forms.