Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors (IOA-289 and PF-8380) against DMSO treated controls

ABSTRACT: Autotaxin (ATX), encoded by ENPP2, catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME). ATX is a clinical target in pancreatic ductal adenocarcinoma (PDAC), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. PDAC is characterized by a highly fibrotic tumor microenvironment (TME) due to an abundance of cancer associated fibroblasts (CAFs), acting as a barrier to therapy and contributing to the poor survival of PDAC patients. The mechanism by which ATX inhibition influences CAFs and their secretome is still not fully characterized. To identified potential downstream mediators of ATX signaling, we performed RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors, IOA-289 and PF-8380. PF-8380 treatment resulted in a higher number of differentially expressed genes compared to IOA-289 treatment. IOA-289 treatment resulted in only four significantly differentially expressed genes (CTGF, PLIN2, HHIP, and AHNAK). However, only PLIN2, which was upregulated and CTGF, which was downregulated, overlapped between the two ATX inhibitors. As CTGF (connective tissue growth factor) is a pro-fibrotic and pro-tumorigenic factor, it suggests a key role for CAF-derived ATX in promoting autocrine and paracrine pro-tumorigenic signaling in PDAC.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Fanny Volat

PROVIDER: E-MTAB-14494 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Autotaxin (ATX) has been reported to act as a motility and growth factor in a variety of cancer cells. The ATX protein acts as a secreted lysophospholipase D (lysoPLD) by converting lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which signals via G-protein coupled receptors and has important functions in cell migration and proliferation. The current study demonstrates that ATX expression is upregulated and functionally active in FLT3-ITD+ human blasts. ATX expression was also found in normal human CD34+ progenitor cells and selected myeloid and lymphoid subpopulations. Stable transduction of mutant FLT3-ITD increased ATX mRNA in selected cell lines, whereas inhibition of FLT3-ITD signaling by sublethal doses of PKC412 led to a significant down-regulation of ATX. Moreover, results indicate that the Jun N-terminal kinase (JNK) is an important mediator between FLT3 signaling and ATX. In the presence of LPC, ATX expression led to a significant increase of proliferation. LPA caused proliferation of all tested cell lines, regardless of ATX expression and induced chemotaxis in human leukemic cell lines and human CD34+ progenitors. LPC increased chemotaxis, in cells with high expression of endogenous and exogenous ATX, by at least 80% demonstrating the autocrine effect of ATX expression. Inhibition of ATX using a small molecule inhibitor induced selective killing of ATX-expressing cell lines and reduced the motile phenotype observed in this cells. Our data suggest that the production of bioactive LPA through ATX is involved in controlling proliferation and migration during hematopoiesis and that deregulation contributes to the pathogenesis of AML. AML Classes: Molecular/cytogenetic group of acute myeloid leukemia, either internal tandem duplication (FLT3) or FLT3 point mutation (D835) or normal karyotype (NK) or t(8;21) transclocation (t821) or monosomy 7 (mono7) or inversion on chromosome 16 (inv16) or high leukocyte count normal karyotype (HL). FAB (French-American-British) Classification system for acute myeloid leukemia is provided for each sample.

Dataset Information

RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors (IOA-289 and PF-8380) against DMSO treated controls

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