Molecular Cancer Research最新文献

Myeloid-derived suppressor cells (MDSC) are one of the major contributors to the immunosuppressive microenvironment of breast cancer. MDSCs have unique mechanisms for each breast cancer metastasis site, and lipid metabolism acts as an energy source necessary to perform the role of MDSCs. In addition, MDSCs show different characteristics depending on the breast cancer subtype. Currently, there is no clear understanding of MDSCs tailored to subtypes and metastatic sites in breast cancer. In this study, we reviewed the biology and function of MDSCs revealed in breast cancer, focusing on metastasis and lipid metabolism, and discussed treatments targeting MDSCs. Understanding MDSC properties and functions by breast cancer subtype and metastatic niche will be a prerequisite for taking the next step in subdividing patients with breast cancer and providing customized treatment.

FOXA1 is a pioneer transcription factor essential for chromatin accessibility and transcriptional regulation in hormone-driven cancers. In breast cancer, FOXA1 plays a central role in facilitating nuclear receptor binding, reprogramming enhancer landscapes, and promoting transcriptional changes associated with therapy resistance. Whereas FOXA1's function has been primarily studied in the context of estrogen receptor-α (ER), its broader protein interaction network remains incompletely defined. In this study, we systematically map FOXA1-interacting proteins in ER-positive breast cancer cells using proximity-dependent biotin labeling (miniTurbo) combined with quantitative LC-MS/MS proteomics. We engineered MCF-7 cell lines stably expressing miniTurbo-tagged FOXA1 at either the N-terminus or C-terminus to ensure comprehensive coverage of interaction interfaces. This approach recovered known FOXA1 partners, including AR, MLL3, YAP1, and GATA3, and identified 157 previously unreported FOXA1 interactors. Notably, 42 of these novel partners, including NR2C2, were significantly associated with poor relapse-free survival in patients with ER-positive breast cancer. To demonstrate the utility of this resource, we characterized the FOXA1-NR2C2 interaction in depth. Integrating chromatin immunoprecipitation sequencing and RNA sequencing, we show that FOXA1 and NR2C2 co-occupy a subset of genomic regions and drive co-regulated transcriptional programs involved in tumor progression. Our study reveals an expanded FOXA1 interactome and new insights into its functional network in breast cancer, providing candidate proteins for further exploration as biomarkers or therapeutic targets.

Implications: These findings expand the FOXA1 interactome in breast cancer and uncover new candidate proteins with potential as biomarkers and therapeutic targets in hormone-driven tumors.

Oncogenesis, tumor progression, and therapy response are shaped by somatic alterations in the cancer genome and features of the tumor-immune microenvironment (TME). How interactions between these two systems influence tumor evolution and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC that systematically integrates genetic cancer drivers and infiltration profiles of immune cells to find pairwise combinations of drivers and TME characteristics that jointly associate with clinical outcomes. By analyzing 8,500 primary tumor samples of 26 cancer types, we report 34 immunogenomic interactions (IGX) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell levels were significantly correlated with patient survival. Subsets of tumor samples defined by some IGXs were characterized by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of immunotherapy target genes. In luminal-A breast cancer, an IGX involving MEN1 deletion combined with reduced levels of neutrophils associated with lower progression-free survival and deregulation of immune signaling pathways, as observed in two independent cancer genomics datasets. These results showcase the ability of PACIFIC to integrate complex multi-omics datasets with clinical information, enabling the identification of clinically relevant IGXs. Such interactions provide a rich set of hypotheses for mechanistic studies and the development of biomarkers and therapeutic targets.

Implications: Co-occurrence patterns of cancer drivers and TME characteristics highlight synergistic interactions with prognostic potential.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapies. Although aberrant N-glycosylation is a hallmark of malignancy, the specific roles of core-fucosylated (CF) and outer arm-fucosylated (OAF) N-glycans in TNBC progression and patient survival remain underexplored. This study utilized multiplexed glycomics by matrix-assisted laser desorption/ionization imaging mass spectrometry to spatially profile 348 N-glycans in 59 TNBC tumors with clinical characteristics including survival data. Spatial analysis revealed distinct localization patterns of CF and OAF isomers within tumor microenvironments. Strikingly, OAF glycans, but not CF, were strongly associated with tumor stage, with expression increasing from stage I to III and then declining in stage IV. Furthermore, 68 N-glycans were significantly associated with survival outcomes; 36 (52%) of these were OAF-modified, including polylactosamine structures previously linked to metastasis in breast cancer. High expression of OAF polylactosamines correlated with poor prognosis and was detectable in early-stage TNBC tumors, underscoring their potential as prognostic biomarkers.

Implications: These findings demonstrate that OAF N-glycans are dynamic, structure-specific markers of TNBC progression and survival, and their early detection and strong prognostic value highlight potential utility in patient stratification and personalized therapy.

In ovarian cancer, resistance to conventional treatments has prompted the search for alternative targets and/or cells within the tumor microenvironment that could enhance tumor cell death. Ferroptosis, an iron-dependent, lipid peroxide-triggered form of cell death, is one such pathway. Cancer-associated fibroblasts (CAF) are key stromal cells in the ovarian tumor microenvironment that can affect therapeutic responses. Using various genetic approaches, we generated multiple DDR2-expressing and DDR2-deficient human ovarian tumor and mouse breast tumor CAFs. We found that DDR2 expression in CAFs protects these cells from ferroptosis by regulating the xCT-GSH-GPX4 antioxidant pathway and cellular iron metabolism. Specifically, DDR2 regulates xCT expression through noncanonical p62-dependent NRF2 activation and the labile iron pool by controlling ferritinophagy. CAFs secrete factors, in a DDR2-dependent manner, that provide protection to ovarian tumor cells against olaparib-induced cell death, a clinically relevant PARP inhibitor (PARPi). Finally, we found that high expression of DDR2 in the stromal cells of human ovarian tumors is associated with poor response to PARPi in clinical trials. These findings suggest that ferroptotic regulation by DDR2 in ovarian tumor CAFs could affect therapeutic sensitivity and resistance to PARPi.

Implications: The action of the collagen receptor tyrosine kinase DDR2 in CAFs confers PARPi protection to ovarian tumor cells by protecting CAFs from ferroptosis.

Prostate tumor cells produce cholesterol de novo, and statin therapy targets the initial rate-limiting enzyme in this process, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). The extent to which the expression of HMGCR in prostate tumors could influence progression and predict the potential antineoplastic effects of statins remains unclear. In a prospective cohort study of 1,098 men diagnosed with primary prostate cancer from 1982 to 2009 in the Health Professionals Follow-up Study and Physicians' Health Study, 16% of prostate tumors showed strong HMGCR staining intensity, and 31% showed no staining. HMGCR expression was higher in tumors with PTEN loss but did not differ by statin use or long-term dietary cholesterol or saturated fat intake. Participants were followed for lethal events (distant metastases or prostate cancer-related death) over up to 32 years, and 96 lethal events occurred in those without metastases at diagnosis. Strong HMGCR expression was associated with higher rates of lethal prostate cancer (HR, 2.2; 95% confidence interval, 1.3-3.7), adjusting for age at diagnosis and Gleason score but without a linear dose response. In vitro, in the LNCaP human prostate cancer cell line, atorvastatin affected tumor cell viability in cells with experimentally lowered HMGCR expression. This study corroborates that high cholesterol synthesis in prostate tumor cells is associated with PTEN loss, aggressive tumor characteristics, and a greater risk of lethality.

Implications: High expression of HMGCR, the first rate-limiting enzyme of cholesterol synthesis, is a feature of prostate tumors that are more likely to progress to metastatic disease or death from prostate cancer.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a pivotal enzyme in one-carbon metabolism, is significantly overexpressed in tongue squamous cell carcinoma (TSCC) and correlates with poor patient prognosis. Functional studies demonstrate that MTHFD2 drives TSCC proliferation and migration in vitro and in vivo, while its inhibition suppresses tumor progression. Mechanistically, MTHFD2 orchestrates a dual post-translational modification cascade: through its enzymatic activity, it simultaneously induces FOXO1 hypermethylation and ubiquitination, ultimately triggering ubiquitin-proteasome degradation of this tumor suppressor. This methylation-primed degradation axis is clinically validated by the inverse MTHFD2-high/FOXO1-low expression pattern in TSCC specimens, which predicts adverse outcomes. Critically, pharmacological inhibition of MTHFD2 (e.g., DS18561882) blocks FOXO1 degradation, establishing the MTHFD2-FOXO1 axis as a promising therapeutic target for TSCC through its novel metabolic-epigenetic regulatory mechanism. Implications: This study identifies the MTHFD2-FOXO1 axis as a druggable metabolic-epigenetic pathway in TSCC, providing both a prognostic marker and a therapeutic target.

Retinoblastoma (RB) is the most common pediatric eye cancer. Most cases of RB are initiated by bi-allelic mutational inactivation of the RB1 gene, yet most RB tumors harbor additional genomic aberrations that may promote tumor progression. After RB1, the gene that is most commonly mutated gene in RB is BCOR, which is mutated in approximately 20% of RB tumors and is associated with a more aggressive tumor phenotype and worse patient outcomes. Despite its importance, little is known about the role of BCOR in RB. Here, we interrogated BCOR in low passage RB cell lines using mass spectrometry, chromatin immunoprecipitation sequencing, and RNA sequencing. We show that the BCOR protein interacts with members of the ncPRC1.1 Polycomb Repressive Complex and localizes at gene loci with traditionally activating and repressing chromatin markers. Loss of BCOR downregulates the expression of genes associated with cell cycle regulation and upregulates genes associated with hypoxic adaptation. We conclude that BCOR mutations slow cell proliferation and drive hypoxic adaptation in RB via epigenetic mechanisms that may be amenable to targeted therapy. Implications: This study reveals that BCOR may play a noncanonical, multi-faceted role in retinoblastoma with implications in cell cycle, differentiation, and hypoxic adaptation, ultimately shedding insight into its molecular framework for future therapeutic strategies.

The pediatric and adolescent liver cancers, hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC), respectively, are dangerous diseases requiring aggressive surgery, when feasible, and nontargeted toxic chemotherapy for a chance of cure due to insufficient knowledge of underlying molecular mechanisms. We have previously reported the essential role of ph-S675-β-catenin in the reorganization of genomic structure in HBL and FLC by oncogenic activation via chromosomal regions called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGR/ALCD). In FLC, the fusion DNAJB1-PKAc (J-PKAc) oncoprotein phosphorylates β-catenin at Ser675, triggering such CEGRs/ALCDs-mediated activation of oncogenes. In this study, we found that all members of the cohesin ring-CTCF, Rad21, SMC1, SMC3, and STAG1-and β-catenin-TCF4 are bound to CEGRs/ALCDs of oncogenes in HBL and FLC, as well as many other cancers, and that this binding increases transcription. Examination of a large cohort of HBL and FLC samples revealed that cohesin ring expression is dramatically elevated in the majority. The cohesin ring, as well as the ph-S675-β-catenin-TCF4-p300 complex, is detected on both the promoter and intron-located CEGRs/ALCDs of NRF2 and Thy1, correlating with increased transcription. This suggests that the cohesin ring creates the DNA loop for oncogene activation. The inhibition of the cohesin ring by JQ1 reduces the proliferation of HBL and FLC cells in culture, as well as cells expressing the FLC-specific J-PKAc fusion oncogene.

Implications: These studies provide evidence that J-PKAc-β-catenin and the cohesin ring cooperate in oncogenic activation for both HBL and FLC.

Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)-host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV positive), 11 (20.4%) of whom had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5%), FAT1 (n = 9, 16.7%), KMT2D (n = 9, 16.7%), and RB1 (n = 7, 13.0%). In 36 of 44 (81.8%) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into Catalogue of Somatic Mutations in Cancer tier 1 or tier 2 cancer-related human genes.

Implications: A combined genomics score incorporating tumor mutational burden and copy-number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status; thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.