The EU database of processing factors for pesticide residues has been set up in 2018 and was now updated for the first time. 1301 processing studies were added to the database extending it to more than double size. The studies were either provided to EFSA in MRL setting procedures or pesticide peer reviews or they were submitted to BfR in the framework of national or zonal authorization procedures. All studies have been thoroughly (re‐)evaluated with respect to the well‐proven set of quality parameters already applied in the EU database. Processing factors were derived and their reliabilities judged. For newly reported processes such as palm oil and palm kernel oil production, sugar production from sugar cane and sake production from rice the representative processes have been described. Furthermore, new processed matrices such as selected cooked vegetables or pulses have been added to the database and to the accompanying documents.
Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.
Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.
Cancer metastasis is responsible for >90% of cancer deaths and remains a major treatment challenge. In search of new drivers of metastasis we identified the novel, previously undescribed gene Metastasis-Associated in Colon Cancer 1 (MACC1) in human colorectal cancer (CRC). MACC1 induces fundamental processes like proliferation, migration, invasiveness and metastasis in xenografted and transgenic mice. MACC1 has been established by us and many other groups as key player, prognostic and predictive biomarker for tumor progression and metastasis in >20 solid cancer types. Proof-of-concept for MACC1 as a therapeutic target to restrict cancer progression and metastasis was provided by transcriptional and post-transcriptional downregulation of MACC1 for several solid cancers, including CRC. Specific inhibitors targeting MACC1 post-translational protein modifications to restrict tumor growth and metastasis are not identified so far. Here we report the identification of MACC1 as a newly identified substrate of the kinase MEK1 (MAP2K1). MEK1 directly phosphorylates MACC1 leading to accelerated and increased ERK1 activation. Mutating three potential hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1 dependent target gene expression like MET, cell proliferation and motility in cell culture and importantly, metastasis in mouse xenograft models. Targeting MEK1 by RNAi or by clinically applicable MEK1 inhibitors like AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation. Our findings demonstrate that MAP kinase signaling is not linearly leading only to ERK activation, but branches at the level of MEK1. In summary, MACC1 tyrosine phosphorylation is decisive for tumor growth and metastasis. The fundamental finding of MACC1 being a newly identified MEK1 substrate opens new therapeutic options with potential for clinical translation. Targeting MACC1 tyrosine phosphorylation using MEK1 inhibitors thereby intervening in MACC1-induced metastasis aims at the ultimate goal of personalized therapies for inhibition of cancer progression and metastasis, resulting in improved patient survival. Since MACC1 is confirmed as decisive driver for tumor growth and metastasis in a variety of solid cancers, the findings made here for CRC might be translated to further solid tumor types. The usefulness of MACC1 as therapeutic target towards MEK1 inhibitor treatment requires confirmation in clinical trials. Citation Format: Dennis Kobelt, Daniel Perez-Hernandez, Claudia Fleuter, Mathias Dahlmann, Fabian Zincke, Janice Smith, Rebekka Migotti, Susen Burock, Wolfgang Walther, Gunnar Dittmar, Ulrike S. Stein. Cancer metastasis driven by the novel MEK1 substrate MACC1 is restricted by clinically applicable MEK1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2000.
Background: Numerous clinical trials have considered the potential linkages between statins and cancer. Despite some evidence for reduced mortality associated with statin use, the results thus far have been somewhat inconclusive and not easily comparable, thus hampering the emergence of a consensus. We suspect that this uncertainty would be reduced, and greater clarity achieved (e.g. regarding clinical best practices and standards-of-care), were we to have a reliable, causal biomarker that could help identify those individual patients who might benefit from statin use during cancer treatment. Methods and Findings: In the joint experimental and statistical analysis reported here, we assessed the inhibitory potential of various statins on the expression of a tumor enhancer known as MACC1, taking into account the molecular functions of this key metastasis-associated protein. To assess any effects of statins in cancer prevention (observationally), we also performed a retrospective, two-center, nested case-control study, focusing on medical centers in Berlin, Germany and Virginia, USA. Among nearly a half-million patient visits, over a decade-long period, cancer patients were identified and analyzed in comparison to patients without cancer diagnoses. Odds ratios (OR) and hazard ratios (HR) for cancer were computed for patients with and without statin intake, accounting for potential confounders. Finally, we also extended these analyses of our trans-Atlantic cohort by utilizing real-world data from 132,072 cancer patients with statins available on the TriNetX platform. Experimental work revealed that statins inhibit MACC1 mRNA levels and protein expression, resulting in reduced MACC1-induced phenotypic functions, such as motility and proliferation. Moreover, we found that statins restrict colorectal cancer (CRC) growth and metastasis in xenografted mice. The cohort data that we gathered at the German and U.S. centers enabled analysis of 53,113 cancer patients and matched controls. These were extracted, aggregated, and 1:1 matched (by age/gender) in order to build propensity-score matched sub-cohorts, to mitigate confounder bias. Based on this real-world evidence (RWE), we found that atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin were associated with a 50% reduced overall risk for developing cancer (OR 0.5, CI 0.48-0.51). The strongest association of reduced cancer risk was found for (i) liver cancer (OR 0.35, 0.29-0.43), (ii) secondary neoplasms of respiratory and digestive organs (OR 0.42, 0.34-0.45), and (iii) colorectal cancer (OR 0.44, 0.39-0.5). The effect of atorvastatin (OR 0.3, 0.28-0.32) exceeded other considered statins, even after exclusion of aspirin as the strongest confounder (OR 0.63, CI 0.57-0.7). Additionally, we note that those patients taking statins have a 38% decreased risk of death (HR 0.64, 0.48-0.86). Conclusions: Our data, which offer evidence for cancer-preventative and anti-metastatic effects of statins, lead us to suggest that these medications should be considered in treating some types of cancers. In addition, MACC1 may serve as a potentially helpful biomarker for purposes of patient stratification (and personalized treatment). A more definitive test of these proposed ideas could come from prospective, randomized clinical trials.
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