Molecular Oncology最新文献

Prostate cancer, the most common malignancy in men, has a relatively favourable prognosis. However, when it spreads to the bone, the survival rate drops dramatically. The development of bone metastases leaves patients with aggressive prostate cancer, the leading cause of death in men. Moreover, bone metastases are incurable and very painful. Hepatocyte growth factor receptor (MET) and fusion of genes encoding E26 transformation-specific (ETS) transcription factors are both involved in the progression of the disease. ETS gene fusions, in particular, have the ability to induce the migratory and invasive properties of prostate cancer cells, whereas MET receptor, through its signalling cascades, is able to activate transcription factor expression. MET signalling and ETS gene fusions are intimately linked to high-grade prostate cancer. However, the collaboration of these factors in prostate cancer progression has not yet been investigated. Here, we show, using cell models of advanced prostate cancer, that ETS translocation variant 1 (ETV1) and transcriptional regulator ERG (ERG) transcription factors (members of the ETS family) promote tumour properties, and that activation of MET signalling enhances these effects. By using a specific MET tyrosine kinase inhibitor in a humanised hepatocyte growth factor (HGF) mouse model, we also establish that MET activity is required for ETV1/ERG-mediated tumour growth. Finally, by performing a comparative transcriptomic analysis, we identify target genes that could play a relevant role in these cellular processes. Thus, our results demonstrate for the first time in prostate cancer models a functional interaction between ETS transcription factors (ETV1 and ERG) and MET signalling that confers more aggressive properties and highlight a molecular signature characteristic of this combined action.

Neoadjuvant chemotherapy (NAT) is increasingly used for the treatment of non-metastatic pancreatic ductal adenocarcinoma (PDAC) and is established as a standard of care for borderline resectable and locally advanced PDAC. However, full exploitation of its clinical benefits is limited by the lack of biomarkers that assess treatment response. To address this unmet need, global metabolomic profiling was performed on tumor tissue and paired serum samples from patients with treatment-naïve (TN; n = 18) and neoadjuvant leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX)-treated (NAT; n = 17) PDAC using liquid chromatography mass spectrometry. Differentially abundant metabolites (DAMs) in TN versus NAT groups were identified and their correlation with various clinical parameters was assessed. Metabolomics profiling identified 40 tissue and five serum DAMs in TN versus NAT PDAC. In general, DAMs associated with amino acid and nucleotide metabolism were lower in NAT compared to TN. Four DAMs-3-hydroxybutyric acid (BHB), 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), glycochenodeoxycholate and citrulline-were common to both tissue and serum and showed a similar pattern of differential abundance in both groups. A strong positive correlation was observed between serum carbohydrate 19-9 antigen (CA 19-9) and tissue carnitines (C12, C18, C18:2) and N8-acetylspermidine. The reduction in CA 19-9 following NAT correlated negatively with serum deoxycholate levels, and the latter correlated positively with survival. This study revealed neoadjuvant-chemotherapy-induced changes in metabolic pathways in PDAC, mainly amino acid and nucleotide metabolism, and these correlated with reduced CA 19-9 following neoadjuvant FOLFIRINOX treatment.

The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell-free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE-4.5 included mCRC patients with BRAF V600E mutation detected by tissue-based analyses. Liquid biopsies (LBs) were collected at baseline (pre-treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)-certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression-free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild-type patients. Follow-up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild-type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC.

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK⁺ non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS-mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine-protein kinase erbB-3 (HER3) were also identified in DTP cells, and co-treatment with EGFR-TKI plus ALK-TKI enhanced ROS levels. Triple combination with an ALK-TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK⁺ NSCLC to prevent the development of resistance to ALK-TKIs and lead to tumor eradication.

Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.

The mechanisms that work alongside BRAF^V600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal Braf^V600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with Braf^V600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with Braf^V600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.

The Kirsten rat sarcoma (KRAS) oncogene was considered "undruggable" until the development of sotorasib, a KRAS^G12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRAS^G12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib- and MRTX1133-resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2-mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS-mutant pancreatic cancer.

Somatic multigene analysis by next-generation sequencing (NGS) is routinely integrated in medical oncology for clinical decision-making. However, with the fast-growing number of recommended and required genes as well as pan-cancer biomarkers, small panels have become vastly insufficient. Comprehensive genomic profiling (CGP) is, thus, required to screen for clinically relevant markers. In this multicentric study, we report on an extensive analysis across seven centers comparing the results of the novel OncoDEEP CGP assay with the diagnostically validated TruSight Oncology 500 (TSO500) kit on 250 samples. Overall concordance was 90% for clinically relevant gene variants and >96% for more complex biomarkers. Agreement for fusion detection was 94% for the 11 overlapping clinically actionable driver genes. The higher coverage uniformity of OncoDEEP compared to TSO500 allows users to pool more samples per sequencing run. Tertiary data analysis, including reporting, is integrated in the OncoDEEP solution, whereas this is an add-on for TSO500. Finally, we showed that, analytically, the OncoDEEP panel performs well, thereby advocating its use for CGP of solid tumors in diagnostic laboratories, providing an all-in-one solution for optimal patient management.

The presence of cancer stem cells is linked to aggressive disease and higher risk of recurrence, and multiple markers have been proposed to detect cancer stem cells. However, a detailed evaluation of the expression patterns and the prognostic value of markers relevant for endometrial cancer is lacking. As organoid models are suggested to be enriched in cancer stem cells, such models may prove valuable to define tissue-specific cancer stem cells. To address this, imaging mass cytometry and multiplex single-cell analyses were performed on an endometrial cancer patient series including both tumor biopsies and corresponding patient-derived organoids. An antibody panel focused on cancer stem cell markers was used to identify cancer stem cell phenotypes. Over 70% of epithelial cells in the tumor biopsies expressed at least one putative cancer stem cell marker. We identified distinct cancer cell phenotypes with heterogeneous expression within individual patients and between patient samples. Few differences in the distribution of cancer cell phenotypes were observed between tumor biopsies and corresponding organoids. Cells expressing aldehyde dehydrogenase 1 (ALDH1) were more prevalent in high-grade tumors, while expression of CD44 was more prevalent in grade 1 tumors. Spatial analysis revealed significantly less interaction between ALDH1- and CD44-expressing cells. Gene expression data was used to further investigate selected markers. CD44 gene expression was associated with a favorable prognosis and was further validated using immunohistochemistry. High expression of CD44 was significantly associated with better survival. The general high expression of proposed stem cell markers may indicate alternative roles for these in endometrial cancer.

Immune checkpoint inhibitors have demonstrated limited efficacy in overcoming immunosuppression in patients with epithelial ovarian cancer (EOC). Although certain patients experience long-term treatment benefit, reliable biomarkers for responder pre-selection and the distinction of dominant immunosuppressive mechanisms have yet to be identified. Here, we used a 40-marker suspension mass cytometry panel to comprehensively phenotype peripheral blood leukocytes sampled over time from patients with relapsed EOC who underwent combination oleclumab (anti-CD73) and durvalumab (anti-PD-L1) immunotherapy in the NSGO-OV-UMB1/ENGOT-OV30 trial. We found that survival duration was impacted by baseline abundances of total peripheral blood mononuclear cells. Longitudinal analyses revealed a significant increase in CD14⁺CD16^- myeloid cells during treatment, with significant expansion of monocytic myeloid-derived suppressor cells occurring in patients with shorter progression-free survival, who additionally showed a continuous decrease in central memory T-cell abundances. All patients demonstrated significant PD-L1 upregulation over time on most T-cell subsets. Higher CD73 and IDO1 expression on certain leukocytes at baseline significantly positively correlated with longer progression-free survival. Overall, our study proposes potential biomarkers for EOC immunotherapy personalization and response monitoring; however, further validation in larger studies is needed.