title: MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up-regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin.
abstract: Extensive desmoplasia is a prominent pathological characteristic of pancreatic cancer (PC) that not only impacts tumor development, but therapeutic outcome as well. Recently, we demonstrated a novel role of MYB, an oncogenic transcription factor, in PC growth and metastasis. Here we studied its effect on pancreatic tumor histopathology and associated molecular and biological mechanisms. Tumor-xenografts derived from orthotopic-inoculation of MYB-overexpressing PC cells exhibited far-greater desmoplasia in histological analyses compared with those derived from MYB-silenced PC cells. These findings were further confirmed by immunostaining of tumor-xenograft sections with collagen-I, fibronectin (major extracellular-matrix proteins), and α-SMA (well-characterized marker of myofibroblasts or activated pancreatic stellate cells (PSCs)). Likewise, MYB-overexpressing PC cells provided significantly greater growth benefit to PSCs in a co-culture system as compared with the MYB-silenced cells. Interrogation of deep-sequencing data from MYB-overexpressing versus -silenced PC cells identified Sonic-hedgehog (SHH) and Adrenomedullin (ADM) as two differentially-expressed genes among others, which encode for secretory ligands involved in tumor-stromal cross-talk. In-silico analyses predicted putative MYB-binding sites in SHH and ADM promoters, which was later confirmed by chromatin-immunoprecipitation. A cooperative role of SHH and ADM in growth promotion of PSCs was confirmed in co-culture by using their specific-inhibitors and exogenous recombinant-proteins. Importantly, while SHH acted exclusively in a paracrine fashion on PSCs and influenced the growth of PC cells only indirectly, ADM could directly impact the growth of both PC cells and PSCs. In summary, we identified MYB as novel regulator of pancreatic tumor desmoplasia, which is suggestive of its diverse roles in PC pathobiology.
authors.affiliation: From the Departments of Oncologic Sciences and.
authors.forename: Arun
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: From the Departments of Oncologic Sciences and.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Srivastava
authors.affiliation: From the Departments of Oncologic Sciences and Departments of Biochemistry and Molecular Biology and.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: From the Departments of Oncologic Sciences and.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tyagi
authors.affiliation: From the Departments of Oncologic Sciences and.
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.affiliation: Pathology, College of Medicine, University of South Alabama, Mobile, Alabama 36688.
authors.forename: James E
authors.initials: JE
authors.lastname: Carter
authors.affiliation: Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604 and.
authors.forename: Moh'd
authors.initials: M
authors.lastname: Khushman
authors.affiliation: From the Departments of Oncologic Sciences and Departments of Biochemistry and Molecular Biology and asingh@health.southalabama.edu.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
mesh_terms: D053607:Adrenomedullin / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000096:biosynthesis* / Q000235:genetics; D064593:Heterografts; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D020626:Oncogene Proteins v-myb / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D020218:Response Elements; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C507862:ADM protein, human; D053823:Hedgehog Proteins; D020626:Oncogene Proteins v-myb; C509239:SHH protein, human; D053607:Adrenomedullin
keywords: ADM; MYB; desmoplasia; gene regulation; pancreatic cancer; sonic hedgehog (SHH); transcription factor; tumor microenvironment