Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.

Detection and Characterization of a Mycobacterial L-Arabinofuranose ABC Transporter Identified with a Rapid Lipoproteomics Protocol

“…Likewise, by using a minimum logfold-change, we intended to focus on proteins, for which strong (high amplitude) regulation is being observed. The combination of a p-value cutoff with a log fold-change cutoff has proven to be very powerful in a number of quantitative proteomic studies (Drendel et al, 2018;Oria et al, 2018;Zhang et al, 2019).…”

Role of Kallikrein 7 in Body Weight and Fat Mass Regulation

“…Formalin-fixed, paraffin embedded specimens of iWAT and eWAT depots of control or AT Klk7 −/− mice were processed [ 27 ] and liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed as described [ 28 ]. Each group consisted of four biological replicates.…”

First report on establishment and characterization of a carcinosarcoma tumour cell line model of the bladder

“…Samples were lysed in 100 mM HEPES, 5 mM DTT, 0.1% RapiGest using a Precellys homogenizer, followed by heat incubation (85 °C, 90 min), trypsination, alkylation, acidic RapiGest degradation, and desalting using StageTips as reported in Ref. 29 . Mass spectrometry and data analysis using MaxQuant were performed as described in Ref.…”