Molecular Oncology

Histone-lysine N-methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial-to-mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion and stemness in a transforming growth factor beta (TGF-β)-independent manner...

Mortality from melanoma is associated with metastatic disease, but the mechanisms leading to spreading of the cancer cells remain obscure. Spatial profiling revealed that melanoma is characterized by a high degree of heterogeneity, which is established by the ability of melanoma cells to switch between different phenotypical stages. This plasticity, likely a heritage from embryonic pathways, accounts for a relevant part of the metastatic potential of these lesions, and requires the rapid and efficient reorganization of the transcriptional landscape of melanoma cells...

Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed...

Clinically, the osteolytic phenotype is rare in prostate cancer (PCa), and the prognosis is generally worse than that of the osteoblastic phenotype. Osteoblastic prostate cancer (BPCa) is a major type of bone metastasis. Several factors responsible for osteogenesis have been identified, but the molecular mechanism of osteoblastic bone metastasis in PCa is not fully understood. Here, we show the osteogenic and tumor-suppressive roles of SERPINA3 and LCN2 in BPCa. In a co-culture of osteoblasts (OBs) and BPCa cells, SERPINA3 and LCN2 were remarkably upregulated in BPCa via OB-derived extracellular vesicles (EVs), while they were not in the co-culture of OBs and osteolytic prostate cancer (LPCa) cells...

Traditional immunotherapies provide clinical benefits to only a few patients with solid tumors, highlighting the urgent need for more effective approaches. Traditional immunotherapies rely on the presentation of cancer antigens, with neoantigens being highly important in this context as they are specific to malignant tissue but not healthy tissue. The quantity of neoantigens is often associated with clinical benefit, but it cannot fully explain or predict patient response. In this Viewpoint, we highlight several qualitative aspects that should be considered in neoantigen-based therapy...

Chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), however, chemoresistance compromises its efficacy. The RNA-binding protein Hu antigen R (HuR) could be a potential therapeutic target to enhance the chemotherapy efficacy. HuR is known to mainly stabilize its target mRNAs, and/or promote the translation of encoded proteins, which are implicated in multiple cancer hallmarks, including chemoresistance. In this study, a docetaxel-resistant cell sub-line (231-TR) was established from the human TNBC cell line MDA-MB-231...

Glioblastoma (GBM) is one of the most aggressive types of cancer and exhibits profound genetic and epigenetic heterogeneity, making the development of an effective treatment a major challenge. The recent incorporation of molecular features into the diagnosis of GBM patients has led to an improved categorisation into various tumour subtypes with different prognoses and disease management. In this work, we have exploited the benefits of genome-wide multi-omic approaches to identify potential molecular vulnerabilities existing in GBM patients...

Although early diagnosis and therapeutic advances have transformed the living quality and outcome of cancer patients, the poor prognosis for metastatic patients has not been significantly improved. Mechanisms underlying the complexity of metastasis cannot be simply determined by the straight forward 'cause-and-effect relationships'. We have developed a 'dry-lab-driven knowledge discovery and wet-lab validation' approach to embrace the complexity of cancer and metastasis. We have revealed for the first time that poly-metastatic (POL) melanoma cells can utilize both the secretory protein pathway (S100A11-Sec23a) and the exosomal crosstalk (miR-487a-5p) to transfer their 'poly-metastatic competency' to the oligo-metastatic (OL) melanoma cells, via synergistic co-targeting of the tumor suppressor Nudt21...

A good response to neoadjuvant chemotherapy (NACT) is strongly associated with a higher curative resection rate and favorable outcomes for patients with gastric cancer. We examined the utility of serial circulating tumor DNA (ctDNA) testing for monitoring NACT response and prognosis in stage II-III gastric cancer. Seventy-nine patients were enrolled to receive two cycles of NACT following gastrectomy with D2-lymphadenectomy. Plasma at baseline, post-NACT and after surgery, and tissue at pretreatment and surgery, were collected...

Children with group 3 medulloblastoma (G3 MB) have a very poor prognosis and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin-28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B-lethal-7 (let-7; a microRNA that is a tumor suppressor)-lymphokine-activated killer T-cell-originated protein kinase (PBK; also known as PDZ-binding kinase) axis promotes G3 MB proliferation...

Liver X receptors (LXRs) are nuclear transcription factors important in the regulation of cholesterol transport, and glucose and fatty acid metabolism. The antiproliferative role of LXRs has been studied in a variety of malignancies and may represent a therapeutic opportunity in cancers lacking targeted therapies, such as triple-negative breast cancer (TNBC). In this study, we investigated the impact of LXR agonists alone and in combination with carboplatin in preclinical models of breast cancer. In vitro experiments revealed a dose-dependent decrease in tumor cell proliferation in estrogen receptor (ER)-positive breast cancer cells, whereas LXR activation in vivo resulted in an increased growth inhibitory effect in a basal-like breast cancer model (in combination with carboplatin)...

The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signaling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC model...

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of cancers. Attempts to develop targeted therapies still need to be established. Some oncogenic mechanisms in PDAC carcinogenesis harness the EGFR/ERBB receptor family. To explore the effects on pancreatic lesions, we attempted simultaneous blockade of all ERBB ligands in a PDAC mouse model. To this end, we engineered a molecular decoy, TRAP-FC , comprising the ligand-binding domains of both EGFR and ERBB4 and able to trap all ERBB ligands. Next, we generated a transgenic mouse model (CBATRAP/0 ) expressing TRAP-FC ubiquitously under the control of the chicken beta-actin promoter and crossed these mice with KRASG12D/+ mice (Kras) to generate Trap/Kras mice...

The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients...

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow-up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumor DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp-PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during chemotherapy from 81 patients with locally advanced and metastatic PDAC...

Cancer immunotherapy has revolutionized the treatment of some malignancies. Yet, many tumors do not unfortunately respond to immune-based therapies. Deeper insights into the biology of the immune response to cancer are required to identify novel therapeutic targets and advance immuno-oncology. To do so, we need to study cancer in patient-derived models that can faithfully recapitulate and capture the complexity and heterogeneity of the tumor-immune ecosystem. Platforms facilitating the analysis of the human tumor immune microenvironment of individual patients are crucial...

The formation of organisations and societies within all areas of scientific research facilitates the bringing together of researchers in a given field and serves to aid communication, collaboration, progress of science and career development. Even greater gain can be attained when individual organisations form partnerships to complement each other's activities and to increase the scope of their endeavours. Within this editorial, we highlight the key points of a new partnership formed between two non-profit bodies within cancer research, the European Association for Cancer Research (EACR) and Molecular Oncology, a journal wholly owned by the Federation of European Biochemical Societies (FEBS)...

Genetic rearrangements that fuse an androgen-regulated promoter area with a protein-coding portion of an originally androgen-unaffected gene are frequent in prostate cancer, with the fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2-ERG fusion) being the most prevalent. Conventional hybridization- or amplification-based methods can test for the presence of expected gene fusions, but the exploratory analysis of currently unknown fusion partners is often cost-prohibitive...

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The process of cellular transformation encompasses the acquisition of key and distinctive features, commonly known as hallmarks of cancer. These hallmarks are supported by tumour-intrinsic molecular alterations as well as changes in the microenvironment. Cellular metabolism represents one of the most intimate connections between a cell and the environment. In turn, metabolic adaptation represents a research field of increasing interest in cancer biology. In this viewpoint, I will provide a panoramic perspective of the relevance and repercussions of metabolic alterations in tumours with non-exhaustive illustrative examples and speculate the prospects of cancer metabolism research...