Molecular Cancer Research最新文献

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker ƔH2AX, and alters Androgen Receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer, and that knockdown of OGDHL impairs growth of cell line models of neuroendocrine prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer. Implications: OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and neuroendocrine differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.

Clinical divergence between patients harboring CIC-rearrangements is frequently observed. For example, the prototypical CIC::DUX4 fusion associates with soft tissue tumors while CIC::NUTM1 fusions typically localize to the central nervous system (brain/spinal cord). The basis for these differences is poorly understood due to a lack of molecular tools. To address this need, we generated patient-informed, synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 and validated them in structure-function studies and in genetic zebrafish models. We found that CIC::NUTM1 drives a transcriptional program distinct from that of CIC::DUX4 due to a C-terminal NUTM1 functional domain, CIC::LEUTX weakly activates CIC target genes through LEUTX transactivation sequences, and ATXN1::DUX4 upregulates CIC target genes via the ATXN1 AXH domain. Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity. Implications: These first-generation synthetic tools illuminate partner gene-specific mechanistic biology while providing an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers.

The identification of cancer drivers is a cornerstone to delivery of precision oncology. So far sequencing of renal cell cancer (RCC) has largely been confined to the clear cell subtype of RCC. In contrast, sequencing analyses of the less common forms of RCC, papillary RCC (pRCC) and chromophobe RCC (ChRCC), have so far been limited. We analysed whole genome sequencing data on 164 tumour-normal pairs from the Genomics England 100,000 Genomes Project, providing a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genomic features, including mutational signatures, intra-tumour heterogeneity and analysis of extrachromosomal DNA formation. Our research establishes correlations between genomic alterations and histological diversification and the extent to which genetically-mediated immune escape contributes to the development of these RCC subtypes. Implications: We demonstrate the distinctive genetics which characterises pRCC and ChRCC and how this information has the potential to inform patient treatment and clinical trials.

Endometrioid endometrial cancer (EEC) is the most prevalent gynecological malignancy, yet no targeted therapies are currently approved by the FDA specifically. To identify therapeutic targets for EEC, we performed transcriptomic and proteomic analyses in genetically engineered preclinical cancer models, including uterine-specific Pten-deficient (Ptend/d) mice and Ptend/d mice with additional overexpression of tumor suppressor Mig-6 (Ptend/dMig-6over) mice that develop EEC. Transcriptomic analysis revealed significant inhibition of immune, inflammatory, and angiogenesis pathways with hypoxia-inducible factor-1 (HIF1α) as a key upstream regulator. Interactome and immunoprecipitation analyses identified HDAC1 as a MIG-6-interacting protein that mediates angiogenic signaling in PTEN-deficient endometrial cancer. MIG-6 overexpression suppressed HDAC1 activity and downstream HIF1α-driven angiogenesis. Pharmacologic inhibition of HDAC1 with panobinostat recapitulated the tumor-suppressive effects observed with MIG-6 overexpression. These findings suggest that HDAC1 may represent a potential therapeutic target in EEC and that HDAC inhibition can attenuate early tumor progression and angiogenic signaling in preclinical models. Implications: This study identifies the MIG-6/HDAC1 axis as a key regulator of angiogenesis in EEC, highlighting HDAC1 inhibition as a promising targeted therapeutic strategy for early tumor suppression.

The effects of cis-regulatory alterations in prostate cancer (PCa) are insufficiently characterized, presenting an opportunity to discover driver genes and therapeutic targets. To comprehensively study these effects, we identify genes undergoing allele-specific expression (ASE) in localized PCa and metastatic castration-resistant PCa (mCRPC) samples. By defining recurrent ASE events across prostate tissue and tumor-enriched ASE, we develop CASEDI, a computational framework for prioritizing cancer drivers by integrating ASE and clinical data. CASEDI reveals genes showing recurrent ASE and altered expression in PCa, including AR-regulated and oncogenic ACSM1. mCRPC samples show enrichment of ASE in DNA repair, resistance pathways, and oncogenes and increased frequency of monoallelic expression (MAE) compared to localized tumors. We define an mCRPC gene signature based on MAE status that identifies a subgroup of localized patients with worse prognosis. Using ASE analysis, we expand the landscape of cis-regulatory events in PCa to inform the identification of additional therapeutic targets. Implications: This study develops a framework for identifying cancer drivers using prostate cancer allele-specific expression (ASE) data, generates a comprehensive dataset of ASE in prostate cancer and highlights candidate targets in tumorigenesis and metastasis.

Cancer transcriptomic data are widely leveraged to evaluate the prognostic relevance of targeted genes. However, most basic and translational studies continue to rely on univariable survival analysis, which often fails to capture the full prognostic potential of genes or account for their biological context. Recognizing the complexity of revealing multifaceted prognostic effects, especially when incorporating covariates and variable thresholds, we present the Cancer Gene Prognosis Atlas (CGPA), an interactive tool specifically designed for basic and molecular cancer researchers. CGPA provides an intuitive, user-friendly interface that enables in-depth, customizable prognostic analysis across cancer types. Beyond single-gene analyses, it supports data-driven exploration of gene pairs and gene-hallmark relationships, providing insights into key mechanisms such as synthetic lethality and immunosuppression. CGPA further extends its capabilities to assess multi-gene panels using both public and user-provided data and includes a dedicated portal for cancer immunotherapy datasets. Collectively, CGPA's comprehensive yet user-friendly toolkit empowers researchers to interrogate the prognostic landscape of genes with precision, tailor analyses to specific biological hypotheses, and accelerate biomarker discovery and validation through the integration of both mechanistic-informed and data-driven approaches. Implications: CGPA is a streamlined, interactive platform for multi-context gene-centric prognostic analysis, simplifying biomarker discovery and validation for molecular and basic cancer scientists, and bridging a critical gap in translational cancer research.

Genes encoding ETS family transcription factors are altered by chromosomal rearrangement in 60% to 70% of prostate cancers and nearly all Ewing sarcomas. Ewing sarcoma rearrangements result in chimeric fusion of ETS proteins to the RNA-binding protein EWSR1. Prostate cancer rearrangements result in aberrant expression of ETS proteins such as ETV1, ETV4, ETV5, or ERG that can interact with wild-type EWSR1, suggesting common mechanisms between these diseases. In this study, we find that ETV1, ETV4, and ETV5 can phenocopy EWSR1::FLI1 in Ewing sarcoma cell lines. However, rescue of EWSR1::FLI1 knockdown by ERG requires an ERG mutant that disrupts interaction with polycomb repressive complex 2 (PRC2). This suggests that EWSR1::ERG fusions that drive Ewing sarcoma avoid PRC2 interactions. We then identify an endogenous PRC2/FOXO1 complex and demonstrate that FOXO1 bridges ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provide a mechanism for ERG synergy with PTEN deletion in prostate cancer.

Implications: These findings indicate that ETS transcription factors that drive prostate cancer and Ewing sarcoma utilize similar mechanisms and thus could be targeted by similar therapeutic approaches.

Molecular-based risk stratification of prostate cancer holds significant potential for guiding precision therapeutic strategies. Previous studies revealed that SOX4 activation drives prostate cancer progression in PTEN-deficient tumors through the PI3K-AKT signaling pathway. However, the mechanistic interplay between SOX4 and PTEN, as well as their clinical utility for prognostic stratification, remains to be elucidated. In this study, we revealed that SOX4 expression is increased in patients with prostate cancer with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in patients with prostate cancer. Importantly, patients with prostate cancer exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive prostate cancer subtype associated with an unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput miRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of the miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads to hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses prostate cancer cell proliferation, migration, and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b∼25/PTEN pathway model in promoting prostate cancer progression and propose a potential therapeutic strategy for this high-risk subtype.

Implications: SOX4 suppresses PTEN through the transcriptional upregulation of miR-106b∼25, rendering tumors sensitive to combined inhibition of SOX4 and PI3K-AKT in prostate cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with early metastasis, drug resistance, and poor outcomes. We previously demonstrated a putative tumor-suppressive role for concentrative nucleoside transporter 1 (CNT1) in PDAC. In this study, we demonstrate the regulator of G protein signaling (RGS) 11 as a key target of CNT1, with potent tumor-suppressive properties in PDAC. Compared with normal human pancreas, RGS11 expression is diminished in human PDAC tissues which correspond with the reduced patient survival times. In addition, quasimesenchymal pancreatic tumor cell lines with accelerated growth, metastatic propensity, and innate resistance to nucleoside analogs showed relatively lower RGS11 expression than their epithelial counterparts. Interestingly, RGS11 levels reversibly modulated the epithelial-mesenchymal transition of human PDAC cell lines influencing the chemotherapeutic sensitivities of anti-PDAC drugs. Additionally, stable lentiviral-mediated RGS11 expression reduced the cellular proliferation and colony establishment, increased the apoptotic index, and decreased the migratory and invasive abilities in quasimesenchymal tumor cell lines, whereas RGS11 depletion in epithelial tumor cell lines showed opposite effects. Global transcriptomic analysis revealed RGS11 replenishment in PDAC cells to suppress CD44-directed stemness features with significant reprogramming of the PDAC oncogenic landscape. Furthermore, RGS11 reduced the primary tumor burden and metastatic occurrence in a mouse model of PDAC. Together, these findings uncover RGS11 as a key target of CNT1 that exhibits therapeutic potential for intervention of aggressive PDAC.

Implications: RGS11 identified as a downstream target of a gemcitabine transporter CNT1 exerts potent antitumorigenic features in PDAC with therapeutic and prognostic values.