Fatty acid (FA) uptake and altered metabolism constitute hallmarks of metastasis 1-2 yet it is unclear the biology behind it, or whether all dietary FAs are prometastatic. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma. Unexpectedly, tumours from mice fed a short-term palm oil (PA)-rich diet, or tumour cells briefly exposed to PA in vitro, remain highly metastatic even when serially transplanted (without further exposure to high levels of PA). This PAinduced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A/COMPASS. Bulk, single-cell and positional RNA sequencing indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumour Schwann cells and innervation, two parameters strongly correlated with metastasis but etiologically poorly understood 3-4 . Mechanistically, tumour-associated Schwann cells secrete a specialized pro-regenerative extracellular matrix, whose ablation inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial cellstimulating peptide galanin. In sum, we provide evidence that a dietary metabolite provokes stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a pro-regenerative state of tumour-activated Schwann cells.
Lung cancer is the number one cause of cancer-related deaths worldwide. DNA methylation is an epigenetic mechanism that regulates gene expression, and disease-specific methylation changes can be targeted as biomarkers. We have compared the genome-wide methylation pattern in tumor and tumor-adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32 patients by methylation-sensitive high resolution melting (MS-HRM) analysis. Significant increases in methylation were confirmed for 15 DMRs associated with the genes and genomic regions: OSR1, SIM1, GHSR, OTX2, LOC648987, HIST1H3E, HIST1H3G/HIST1H2BI, HIST1H2AJ/HIST1H2BM, HOXD10, HOXD3, HOXB3/HOXB4, HOXA3, HOXA5, Chr1(q21.1).A, and Chr6(p22.1). In particular the OSR1, SIM1 and HOXB3/HOXB4 regions demonstrated high potential as biomarkers in LAC. For OSR1, hypermethylation was detected in 47/48 LAC cases compared to 1/31 tumor-adjacent normal lung samples. Similarly, 45/49 and 36/48 LAC cases compared to 3/31 and 0/31 tumor-adjacent normal lung samples showed hypermethylation of the SIM1 and HOXB3/HOXB4 regions, respectively. In conclusion, this study has identified and validated 15 DMRs that can be targeted as biomarkers in LAC.
Metastasis remains the leading cause of cancer-related deaths worldwide, and our inability to identify the tumour cells that colonize distant sites hampers the development of effective anti-metastatic therapies. However, with recent research advances we are beginning to distinguish metastasis-initiating cells from their non-metastatic counterparts. Importantly, advances in genome sequencing indicate that the acquisition of metastatic competency does not involve the progressive accumulation of driver mutations; moreover, in the early stages of tumorigenesis, cancer cells harbour combinations of driver mutations that endow them with metastatic competency. Novel findings highlight that cells can disseminate to distant sites early during primary tumour growth, remaining dormant and untreatable for long periods before metastasizing. Thus, metastatic cells must require local and systemic influences to generate metastases. This hypothesis suggests that factors derived from our lifestyle, such as our diet, exert a strong influence on tumour progression, and that such factors could be modulated if understood. Here, we summarize the recent findings on how specific metabolic cues modulate the behaviour of metastatic cells and how they influence the genome and epigenome of metastatic cells. We also discuss how crosstalk between metabolism and the epigenome can be harnessed to develop new anti-metastatic therapies.
Background Within the hematopoietic compartment, fibromodulin (FMOD) is almost exclusively expressed in chronic lymphocytic leukemia (CLL) lymphocytes. We set out to determine whether FMOD could be of help in diagnosing borderline lymphoproliferative disorders (LPD). Methods We established 3 flow cytometry‐defined groups (CLL [n = 65], borderline LPD [n = 28], broadly defined as those with CLLflow score between 35 and −20 or discordant CD43 and CLLflow, and non‐CLL LPD [n = 40]). FMOD expression levels were determined by standard RT‐PCR in whole‐blood samples. Patients were included regardless of lymphocyte count but with tumor burden ≥40%. Results FMOD expression levels distinguished between CLL (median 98.5, interquartile range [IQR] 37.8–195.1) and non‐CLL LPD (median 0.012, IQR 0.003–0.033) with a sensitivity and specificity of 1. Most borderline LPDs were CD5/CD23/CD200‐positive with no loss of B‐cell antigens and negative or partial expression of CD43. 16/22 patients with available cytogenetic analysis showed trisomy 12. In 25/28 (89%) of these patients, FMOD expression levels fell between CLL and non‐CLL (median 3.58, IQR 1.06–6.21). Discussion This study could suggest that borderline LPDs may constitute a distinct group laying in the biological spectrum of chronic leukemic LPDs. Future studies will have to confirm these results with other biological data. Quantification of FMOD can potentially be of help in the diagnosis of phenotypically complex LPDs.
TNF and IL6 when compared with healthy controls, and the ARG1 expression decreased to control levels. At 6 months, the enhancement of TNF and IL6 was observed in either responders (BCR-ABL1 <1%) or non-responders (≥1%), whereas the decrease of ARG1 expression was similar to control levels just in responders. At both 3 and 6 months of treatment, TNF correlated with IL6 expression only in responders (Spearman: r = 0.48, p = 0.0222; and r = 0.57, p = 0.0168, respectively). Furthermore, the longitudinal analysis between diagnosis and 3 months on therapy, those patients who achieve an EMR showed a statistically significant increase of 3 and 13 folds of TNF and IL6, respectively, and a significant 22-fold decrease of ARG1 (Wilcoxon test: p = 0.0444, p = 0.0038 and p = 0.0094, respectively). Summary/Conclusion: Our results are in agreement with a significant immune suppression in CML patients at diagnosis, mediated by MDSCs and their influence on Tregs; also with a stimulatory effect on the immune system after imatinib initiation, especially in those who responded at 3 months. The dynamic of cytokines and, principally, ARG1 may play a role as an immune biomarker to monitor the response to TKI allowing the differentiation of optimal responders.
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