title: Sorafenib resistance and JNK signaling in carcinoma during extracellular matrix stiffening.
abstract: Tumor progression is coincident with mechanochemical changes in the extracellular matrix (ECM). We hypothesized that tumor stroma stiffening, alongside a shift in the ECM composition from a basement membrane-like microenvironment toward a dense network of collagen-rich fibers during tumorigenesis, confers resistance to otherwise powerful chemotherapeutics. To test this hypothesis, we created a high-throughput drug screening platform based on our poly(ethylene glycol)-phosphorylcholine (PEG-PC) hydrogel system, and customized it to capture the stiffness and integrin-binding profile of in vivo tumors. We report that the efficacy of a Raf kinase inhibitor, sorafenib, is reduced on stiff, collagen-rich microenvironments, independent of ROCK activity. Instead, sustained activation of JNK mediated this resistance, and combining a JNK inhibitor with sorafenib eliminated stiffness-mediated resistance in triple negative breast cancer cells. Surprisingly, neither ERK nor p38 appears to mediate sorafenib resistance, and instead, either ERK or p38 inhibition rescued sorafenib resistance during JNK inhibition, suggesting negative crosstalk between these signaling pathways on stiff, collagen-rich environments. Overall, we discovered that β1 integrin and its downstream effector JNK mediate sorafenib resistance during tumor stiffening. These results also highlight the need for more advanced cell culture platforms, such as our high-throughput PEG-PC system, with which to screen chemotherapeutics.
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Thuy V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Sleiman
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Moriarty
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Herrick
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003, USA; Materials Research Science and Engineering Center, University of Massachusetts, Amherst, MA 01003, USA; Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA 01003, USA. Electronic address: speyton@ecs.umass.edu.
authors.forename: Shelly R
authors.initials: SR
authors.lastname: Peyton
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001696:Biomechanical Phenomena; D001940:Breast / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000201:enzymology; D002277:Carcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000737:chemistry*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D003094:Collagen; D000077157:Sorafenib
keywords: Drug resistance; Phosphorylcholine; Poly(ethylene glycol); Stiffness