Multiscale Network Biology
The lab uses computational and experimental methods to understand how mammalian cell signaling and regulation integrate across multiple scales, from the molecular to whole-body level. We combine multiplexed measurements with in vivo imaging and systems-level mathematical modeling to distill principles of cellular communication. We particularly focus on inflammation and cancer, where abnormal signals in multiple cell types promote disease progression and are therapeutically targeted.
We pursue several major goals:
- Understand how regulation at the molecular and cellular level influence global control.
- Translate network analysis into clinically useful information, such as diagnosis, classification, and prediction of drug response.
- Use engineered materials such as nanoparticles to probe and therapeutically exploit multiscale regulation.
Key approaches include the following:
- Multiplexed monitoring of signaling pathways and transcriptional states to dissect network topology.
- Imaging the disease microenvironment to quantify interaction between cell states and soluble signaling factors, microvesicles, and microanatomical structures.
- Whole-body MR, nuclear, and optical imaging for tissue- and organ-level analysis.
- Machine-learning techniques to integrate and interpret complex data-sets across multiple platforms.
- Materials-enabled strategies for selective manipulation of cell behavior at multiple scales.
Our interdisciplinary approach benefits from close collaboration — including with other groups in CSB — to successfully marry computational analyses with appropriate experimental measurements and models of disease.
Ng TSC, Garlin MA, Weissleder R, Miller MA Understanding the EPR effect through image-guided systems pharmacology. Theranostics. 2019;:ePub
Ahrens CC, Chiswick EL, Ravindra KC, Miller MA, Ramseier J, Isaacson KB, Lauffenburger DA, Griffith LG Development and Application of the Metalloprotease Activity Multi-plexed Bead-based Immunoassay (MAMBI). Biochemistry. 2019;58(38):3938-3942 - PMID: 31474112 - DOI: 10.1021/acs.biochem.9b00584
Li R, Attari A, Prytyskach M, Garlin MA, Weissleder R, Miller MA Single‐Cell Intravital Microscopy of Trastuzumab Quantifies Heterogeneous in vivo Kinetics. Cytometry A. 2019;:ePub - PMID: 31423731 - DOI: 10.1002/cyto.a.23872
Miller MA, Mikula H, Luthria G, Li R, Kronister S, Prytyskach M, Kohler RH, Mitchison T, Weissleder R Modular Nanoparticulate Prodrug Design Enables Efficient Treatment of Solid Tumors Using Bioorthogonal Activation. ACS Nano. 2018;12(12):12814-12826 - PMID: 30550257 - PMCID: PMC6307086 - DOI: 10.1021/acsnano.8b07954
Kim HY, Li R, Ng TSC, Courties G, Rodell CB, Prytyskach M, Kohler RH, Pittet M, Nahrendorf M, Weissleder R, Miller MA Quantitative Imaging of Tumor Associated Macrophages and Their Response to Therapy Using 64Cu-Labeled Macrin. ACS Nano. 2018;12(12):12015-12029 - PMID: 30508377 - PMCID: PMC6482841 - DOI: 10.1021/acsnano.8b04338
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Networks of multicellular regulation
Cell signaling pathways, along with the drugs that target them, are often characterized by cross-talk, redundancy, and unpredictable feedback loops. Moreover, behavior can be driven by a combination of physicochemical reaction/diffusion processes, heterogeneity across microenvironmental niches, and intrinsic heterogeneity due to stochasticity. To understand how these features integrate, we develop and apply new computational and experimental strategies that elucidate how cells behave depending on the context.
We particularly focus on growth factors and cytokines implicated in cancer and inflammation — especially as they relate to the innate immune cell biology.
In this work, mathematical modeling has served two main purposes: first, to provide mechanistic insight into how non-linear physicochemical processes and cell-communication networks function, and second, to identify salient biologically-meaningful hypotheses from complex multivariate experimental data. Data-driven statistical methods and machine learning integrate data across platforms and extract useful information.
We use and develop a variety of microscopy methods, fluorescent genetic reporters, and molecular probes to monitor the spatially-regulated dynamics of cell signaling pathways as they occur at sites of disease.
Miller MA, Oudin MJ, Sullivan RJ, Wang SJ, Meyer AS, Im H, Frederick DT, Tadros J, Griffith LG, Lee H, Weissleder R, Flaherty KT, Gertler FB, Lauffenburger DA. Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance. Cancer Discov. 2016 Apr;6(4):382-99. doi: 10.1158/2159-8290.CD-15-0933.
Miller MA, Sullivan RJ, Lauffenburger DA. Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer. Clin Canc Res. 2017 Feb 1;23(3):623-629.
Miller MA, Gadde S, Pfirschke C, Kohler RH, Laughney AM, Pittet M, Farokhzad OC, Weissleder R. Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci Transl Med. 2015 Nov 18;7(314):314ra183. doi: 10.1126/scitranslmed.aac6522.
Miller MA, Meyer A, Beste M, Lasisi Z, Reddy S, Jeng K, Chen CH, Han J, Isaacson K, Griffith LG, Lauffenburger DA. ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling. Proc Natl Acad Sci U S A 2013 May 28;110(22):E2074-83.
Miller MA, Moss ML, Powell G, Petrovich R, Griffith LG, Lauffenburger DA. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain. Sci Rep. 2015 Oct 19;5:15150. doi: 10.1038/srep15150.
Miller M, Hafner M, Sontag E, Davidsohn N, Subramanian S, Purnick P, Lauffenburger D, Weiss R. Design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity. PLoS Comput Biol 8(7): e1002579.
Engineered multi-scale control
We have also integrated strategies to selectively manipulate biological activity at multiple scales. We restrict delivery to particular target tissues at the organ-level, while at a molecular/cellular level we design caged drugs that exhibit regulated activation and subcellular localization. These approaches are largely based on combination treatments and synthetic nanomaterials. In several cases they have been synergistically effective while reducing toxicities.
Miller MA, Zheng Y, Gadde S, Pfirschke C, Kohler RH, Yang KS, Pittet M, Farokhzad OC, Lippard S, Weissleder R. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. Nat Commun. 2015 Oct 27;6:8692. doi: 10.1038/ncomms9692.
Miller MA, Chandra R, Cuccarese MF, Pfirschke C, Engblom C, Stapleton S, Adhikary U, Kohler RH, Pittet MJ, Weissleder R. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci Transl Med. 2017 May 31;9(392). pii: eaal0225. doi: 10.1126/scitranslmed.aal0225.
Miller MA*, Askevold B*, Mikula H, Kohler RH, Pirovich D, Weissleder R. Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 2017 Jul 12;8:15906. doi: 10.1038/ncomms15906.