title: Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias.
abstract: Extracellular matrix stiffness influences biological functions of some tumors. However, it remains unclear how cancer subtypes with different oncogenic mutations respond to matrix stiffness. In addition, the relevance of matrix stiffness to in vivo tumor growth kinetics and drug efficacy remains elusive. Here, we designed 3D hydrogels with physical parameters relevant to hematopoietic tissues and adapted them to a quantitative high-throughput screening format to facilitate mechanistic investigations into the role of matrix stiffness on myeloid leukemias. Matrix stiffness regulates proliferation of some acute myeloid leukemia types, including MLL-AF9+MOLM-14 cells, in a biphasic manner by autocrine regulation, whereas it decreases that of chronic myeloid leukemia BCR-ABL+K-562 cells. Although Arg-Gly-Asp (RGD) integrin ligand and matrix softening confer resistance to a number of drugs, cells become sensitive to drugs against protein kinase B (PKB or AKT) and rapidly accelerated fibrosarcoma (RAF) proteins regardless of matrix stiffness when MLL-AF9 and BCR-ABL are overexpressed in K-562 and MOLM-14 cells, respectively. By adapting the same hydrogels to a xenograft model of extramedullary leukemias, we confirm the pathological relevance of matrix stiffness in growth kinetics and drug sensitivity against standard chemotherapy in vivo. The results thus demonstrate the importance of incorporating 3D mechanical cues into screening for anticancer drugs.
authors: School of Engineering and Applied Sciences, Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138; Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612; Department of Bioengineering, University of Illinois College of Medicine, Chicago, IL 60612.
authors: Jae-Won
authors: JW
authors: Shin
authors: School of Engineering and Applied Sciences, Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138; mooneyd@seas.harvard.edu.
authors: David J
authors: DJ
authors: Mooney
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006244:Hardness; D057166:High-Throughput Screening Assays; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D020100:Hydrogels; C474558:MLL-AF9 fusion protein, human; D009842:Oligopeptides; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; C047981:arginyl-glycyl-aspartic acid; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases
keywords: biomaterials; cancer; drug screening; matrix stiffness; systems pharmacology