title: Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK.
abstract: Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer-associated fibroblasts (CAF). CAFs promote tumor growth, metastasis, and treatment resistance. This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naïve CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF- or R-CAF-conditioned media and assayed for migration, invasion, and viability in vitro Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo R-CAFs increased TC viability, migration, and invasion compared with N-CAFs. In vivo, TCs coinjected with R-CAFs grew larger than those accompanied by N-CAFs. Genomic analysis demonstrated that R-CAFs had increased expression of various inflammatory mediators, similar to the previously described senescence-associated secretory phenotype (SASP). In addition, SASP mediators were found to be upregulated in response to short duration treatment with gemcitabine in both immortalized and primary CAFs. Inhibition of stress-associated MAPK signaling (P38 MAPK or JNK) attenuated SASP induction as well as the tumor-supportive functions of chemotherapy-treated CAFs in vitro and in vivo These results identify a negative consequence of chemotherapy on the PDAC microenvironment that could be targeted to improve the efficacy of current therapeutic regimens.
  
  
  
  Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR.
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Toste
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Nguyen
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Kadera
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Mindy
authors.initials: M
authors.lastname: Duong
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Irmina
authors.initials: I
authors.lastname: Gawlas
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Linh M
authors.initials: LM
authors.lastname: Tran
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Mihir
authors.initials: M
authors.lastname: Bikhchandani
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. tdonahue@mednet.ucla.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D017077:Culture Media, Conditioned; D003841:Deoxycytidine; D000093542:Gemcitabine