Molecular Oncology最新文献

The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)-mediated NAD⁺ regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1) arrested the cell cycle at the G₁/S phase, accompanying upregulation of p21^Cip1 cyclin-dependent kinase inhibitor expression. Mechanistically, a decrease in the NAD⁺/NADH ratio downregulated SIRT3 and SIRT7 function, which suppressed p21^Cip1 expression at the translational and transcriptional levels, respectively, resulting in the upregulation of the antiproliferative molecule. Importantly, high expression levels of the core subunits of CI correlated with poor prognosis in patients with the hormone receptor(+)/human epidermal growth factor receptor 2(-) (HR+/HER2-) subtype of breast cancer. Therefore, NDUFV1 and SIRT3/7 have emerged as promising therapeutic targets against this breast cancer subtype.

Colorectal cancer (CRC) patients with microsatellite-stable (MSS) tumors are mostly treated with chemotherapy. Clinical benefits of targeted therapies depend on mutational states and tumor location. Many tumors carry mutations in KRAS proto-oncogene, GTPase (KRAS) or B-Raf proto-oncogene, serine/threonine kinase (BRAF), rendering them more resistant to therapies. We performed whole-exome sequencing and RNA-Sequencing of 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized CRC patients based on their microsatellite instability (MSI) status, single-nucleotide variations (SNVs)/copy number alterations (CNAs), and pathway/transcription factor activities at the individual patient level. Variants were classified using a computational score for integrative cancer variant annotation and prioritization. Complementing this with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be more strongly activated in MSS patients, whereas Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) molecular cascades were activated specifically in MSI tumors. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified Runt-related transcription factors (RUNX transcription factors) as putative biomarkers in CRC, given their role in the regulation of pathways involved in tumor progression and immune evasion. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impact that KRAS mutations have on immunogenicity, particularly in the MSS patient subgroup, with implications for diagnosis and treatment.

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpass^SM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.

Patient-derived xenografts (PDXs) can be improved by implantation of a humanized niche. Nevertheless, the overall complexity of the current protocols, as well as the use of specific biomaterials and procedures, limits the wider adoption of this approach. Here, we identify the essential minimum steps required to create the humanized scaffolds and achieve successful acute myeloid leukemia (AML) engraftment. We compared seven biomaterials, which included both published and custom-designed materials. The highest level of bone marrow niche was achieved with extracellular matrix gels and custom collagen fiber, both of which allowed for a simple non-surgical implantation. The biomaterial selection did not influence the following AML infiltration. Regarding xenotransplantation, standard intravenous administration produced the most robust engraftment, even for two out of four otherwise non-engrafting AML samples. In contrast, direct intra-scaffold xenotransplantation did not offer any advantage. In summary, we demonstrate that the combination of an injectable biomaterial for scaffold creation plus an intravenous route for AML xenotransplantation provide the most convenient and robust approach to produce AML PDX using a humanized niche.

Late-line treatment in metastatic colorectal cancer (mCRC) can improve prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. We investigated the prognostic role of circulating tumor DNA (ctDNA) in mCRC patients before and during treatment with trifluridine/tipiracil (FTD/TPI). This noninterventional translational biomarker phase II study enrolled 30 mCRC patients (60% male, 40% female). Using a 77-gene panel, ctDNA was detectable in 90% of patients. Tumor levels were assessed based on aneuploidy (ichorCNA) as well as the highest variant allele frequency, and correlated with overall survival (OS). Uni- and multivariate survival analyses were performed with clinical variables. Longitudinal changes in tumor levels over time were analyzed with linear mixed and joint models. The median OS was 8.1 months, with a recorded disease control rate of 30%. High ctDNA levels (≥ 5%) were associated with inferior survival after undergoing FTD/TPI therapy. Elevated tumor level trajectories over time were associated with higher risks of death. Therefore, ctDNA can help identify patients who are unlikely to benefit significantly from this treatment in late-stage disease, thus preventing unnecessary treatments and their associated side effects, ultimately enhancing quality of life.

Patient stratification remains a challenge for optimal treatment of prostate cancer (PCa). This clinical heterogeneity implies intra-tumoural heterogeneity, with different prostate epithelial cell subtypes not all targeted by current treatments. We reported that such cell subtypes are traceable in liquid biopsies through representative transcripts. Expanding on this concept, we included 57 genes representing cell subtypes, drug targets and relevant to resistance as non-invasive biomarkers for stratification. This panel was tested by RT-qPCR (quantitative reverse transcription polymerase chain reaction) in blood of controls and different categories of PCa patients. Overall, circulating transcripts showed predictive value throughout the disease. Those with aggressive pathological features such as intra-ductal carcinoma at diagnosis showed more genes over-expressed. In metastatic patients, signatures of subtypes or resistance were associated with treatments, progression-free survival and overall survival. Altogether, testing markers of cell diversity, an intrinsic feature of tumours, and drug targets via liquid biopsies represents a valuable means to stratify patients and predict responses to current or new therapeutic modalities. Over-expressed drug target genes suggest potential benefit from targeted treatments, justifying new clinical trials to offer patient-tailored strategies to eventually impact on PCa mortality.

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with gastrectomy being the primary treatment option. Sepsis, a systemic inflammatory response to infection, may influence tumor growth by creating an immunosuppressive environment conducive to cancer cell proliferation and metastasis. Here, the effect of abdominal infection on tumor growth and metastasis was investigated through the implementation of a peritoneal metastasis model and a subcutaneous tumor model. In a murine model induced by cecal ligation and puncture (CLP) to simulate the effects of sepsis, we observed significant immune dysregulation, including T-cell exhaustion and the release of myeloid-derived suppressor cells (MDSCs). This immune alteration was associated with increased programmed cell death protein 1 (PD-1) expression on T cells and programmed cell death 1 ligand 1 (PD-L1) expression on MDSCs within the tumor microenvironment, fostering an immune-suppressive environment. Polymorphonuclear MDSCs (PMN-MDSCs) expressing elevated PD-L1 after sepsis demonstrated more substantial suppressive effects on T-cell proliferation than controls. Treatment with anti-PD-1 monoclonal antibodies successfully restored T-cell function, reduced mortality, and decreased metastasis in CLP mice. These findings emphasize the impact of sepsis on tumor progression and suggest targeting the PD-1/PD-L1 axis as a potential therapeutic strategy for managing immune dysfunction in patients with cancer.

The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10-15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGE^SNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGE^SNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10^-5. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.

Transient receptor potential melastatin-4 (TRPM4) ion channel expression is upregulated in prostate cancer (PCa), contributing to increased cell proliferation, migration, adhesion, epithelial-to-mesenchymal transition, cell cycle shift, and alterations of intracellular Ca²⁺ signaling. GEO2R platform analysis of messenger RNA (mRNA) expression of ~ 6350 genes in normal and malignant prostate tissue samples from 15 PCa patients demonstrates that TRPM4 expression is upregulated sixfold and is among the most significantly upregulated genes in PCa. We find that absence of TRPM4 reduced PCa tumor spheroid size and decreased PCa tumor spheroid outgrowth. In addition, lack of TRPM4 increased cell death in PCa tumor spheroids, a phenotype that is absent in two-dimensional (2D) cancer cell systems. Lastly, absence of TRPM4 in PCa cells reduced extravasation and metastatic burden in a preclinical zebrafish cancer model. Taken together, our findings show that TRPM4 is an attractive therapeutic target in PCa and highlights the need for future development of pharmacological tools.

Obesity exacerbates the risk and aggressiveness of many types of cancer. Adipose tissue (AT) represents a prevalent component of the tumor microenvironment (TME) and contributes to cancer development and progression. Reciprocal communication between cancer and adipose cells leads to the generation of cancer-associated adipocytes (CAAs), which in turn foster tumor invasiveness by producing paracrine metabolites, adipocytokines, and growth factors. Interfering with the crosstalk between CAAs and cancer cells is of key relevance in the prevention of tumor progression. The present study aimed to analyze the contribution of peritumoral AT in renal cell carcinoma (RCC) progression in lean versus overweight or obese patients. By isolating human adipose-derived stromal/stem cells from the three groups of patients and performing conditioned medium studies with RCC cells along with in vivo xenograft experiments, we found that peritumoral adipocytes from the three groups show a distinct expression profile of genes. In particular, ADAM metallopeptidase domain 12 (ADAM12) and cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were found to be upregulated in obesity and their silencing reduced RCC cell invasiveness. In conclusion, high ADAM12 and CYP1B1 expressions in the peritumoral adipocytes boost tumor invasiveness and may serve as an indicator of poor prognosis in RCC.