Networks of multicellular regulation and engineered multi-scale control
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.
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.