Molecular Cancer Research最新文献

Cancer remains one of the most pressing global health challenges, with immunotherapy being a promising treatment option. However, numerous clinical challenges such as recurrence and resistance persist, underscoring the urgent need for a deeper understanding of the mechanisms that influence immune responses in cancer. Polo-like kinases (PLKs), a family of enzymes with five members, PLK1 through PLK5, have been implicated in cancer progression, and their inhibition is being actively explored for cancer management. While past studies of the PLK family are largely confined to their role in the cell cycle and corresponding chromatin dynamics, recent research has unveiled important connections between PLKs and cancer immunity, particularly in relation to critical signaling pathways such as interferon (IFN) signaling, immunogenic cell death (ICD), TGF-β signaling, and FAS/FASL signaling. While much of the research has focused on PLK1, additional members of the PLK family are beginning to attract attention due to their potential implications in cancer immunity. Understanding the intricate role of PLKs in cancer immunity is an emerging field with tremendous potential. This review offers a comprehensive overview of current knowledge connecting the members of the PLK family with cancer immunology and provides considerations for further research to uncover how PLK signaling can be strategically targeted to optimize cancer immunotherapy to enhance clinical responses.

An accumulating body of evidence suggests carriers of a pathogenic germline variant (PGV) in BRCA1 or BRCA2 have increased gastric cancer (GC) risk. BRCA1 and BRCA2 are tumor suppressor genes involved in promoting homologous recombination to repair double-stranded DNA breaks. The aim of this investigation was to identify differences within the gastric epithelium and in patient-derived gastric organoids (PDGOs) between BRCA1 and BRCA2 carriers and non-carriers to determine if evidence of early gastric carcinogenesis exists amongst these carriers. First, using gastric epithelial biopsies, BRCA2 carriers were found to harbor higher expression of the proliferative marker Ki-67 within the antral gastric epithelium and strikingly, biopsies from both BRCA1 and BRCA2 carriers displayed a marked increase in double-stranded DNA damage. These results were further explored using PDGOs, where a growth advantage was observed for both BRCA1 and BRCA2 PDGOs compared to non-carrier PDGOs. Furthermore, both BRCA1 and BRCA2 PDGOs displayed a more pronounced enhancement of Ki-67 expression as well as increased double stranded DNA damage compared to non-carrier PDGOs. Importantly, none of the PDGOs showed signs of BRCA1 or BRCA2 loss of heterozygosity, potentially indicating a haploinsufficient phenotype. Taken together, these novel findings suggest that haploinsufficiency in BRCA1 and BRCA2 carriers may lead to DNA damage in the gastric epithelium, which may serve as an early event contributing to GC development. Implications: The elevated risk in GC for BRCA1 and BRCA2 PGV carriers may be due to haploinsufficiency and warrants further investigation into BRCA1 and BRCA2-associated GC.

Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during development. To identify complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of PRC1.1 subunits reduced neuroblastoma growth by inducing a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease. Implications: Our study reveals the potential for utilizing USP7 inhibitors to target epigenetic repression of differentiation programs in neuroblastoma by reducing PRC1 activity.

The P47S missense germline variant of TP53 exists in approximately two percent of Americans of African descent, and may account for the increased cancer risk and poorer response to therapy evident in African-descent populations. In this work we sought to identify personalized therapeutic approaches for cancer containing the P47S variant, with a focus on the most common cancer evident in the P47S mouse, liver cancer. We identify the microtubule targeting agents lexibulin, colchicine, and combretastatin A-4 as three compounds that bind to the colchicine-binding pocket of the a/b tubulin dimer, and which show increased efficacy in a P47S liver cancer cell line compared to parental cells with WT p53. We find evidence for an unusual mechanism underlying this increased efficacy: our data indicate that the P47S variant shows increased ability to bind to the peptidyl-prolyl isomerase PIN1; this leads to decreased PIN1-cyclin D1 complexes in P47S cells, along with increased cell cycle arrest in response to lexibulin. IMPLICATIONS: These findings support the growing literature that particular mutant forms of TP53 may have specific therapeutic vulnerabilities that can be targetable; improved understanding of these unique vulnerabilities can lead to improved understanding of p53 function.

Brain cancers are among the most lethal and challenging malignancies to treat in the clinic. An important impediment to effectively treat brain tumors is the blood-brain tumor barrier (BTB), an interface generated between the blood-brain barrier (BBB) and intra-cranial tumors, creating a tumor-permissive perivascular microenvironment. The BTB loses endothelial barrier properties in an heterogeneous manner across the tumor, but continues to impede effective intra-tumoral drug delivery, dramatically decreasing the potential of many anti-neoplastic pharmaceutics. This review will provide a summary of our current understanding of the molecular composition and cellular architecture of the BTB, focusing on glioblastoma and other high-grade gliomas. We will summarize different multi-omic and spatial studies performed with the goal to reveal unknown traits of the brain cancer-associated vasculature and identify molecular targets of therapeutic relevance. Our work aims to consolidate our current understanding of the vasculature in brain tumors, and the insights held regarding its role in brain cancer biology and therapeutic drug delivery.

Lenvatinib, a first-line targeted therapy for advanced hepatocellular carcinoma (HCC), exhibits significant clinical efficacy. At present, there remains a scarcity of effective treatment options for patients experiencing lenvatinib resistance. This study aims to identify and validate molecular markers capable of predicting the therapeutic response of HCC patients to lenvatinib treatment. We successfully established a lenvatinib-resistant hepatocellular carcinoma cell line (Huh7/LR) through progressive exposure of parental Huh7 cells to lenvatinib. Through RNA sequencing (RNA-seq) analysis, ubiquitin-specific protease 43 (USP43) was ultimately pinpointed as a potential key molecule related to lenvatinib resistance. The expression of USP43 is notably elevated in lenvatinib-resistant HCC cells and tissues, correlating with a poor prognosis for HCC. USP43 promotes the proliferation of HCC cells, suppresses apoptosis, and enhances resistance to lenvatinib. Mechanistically, ETS1 transcriptionally upregulates USP43. USP43 then binds to non-muscle myosin heavy chain 9 (MYH9) and removes its K48-linked polyubiquitination. This stabilizes the MYH9 protein by preventing its degradation through the ubiquitin-proteasome pathway and further activates the AKT/BAD signaling axis, ultimately suppressing apoptosis and conferring lenvatinib resistance. Implications: Targeting the ETS1/USP43/MYH9 axis presents a promising therapeutic strategy to overcome lenvatinib resistance in HCC.

Circular RNA, usually produced through a back-splicing process, is a type of single-stranded RNA that is covalently bonded. Our research indicated that a spliceosome composed of SF3B4 and QKI promoted the back-splicing of FNDC3B, thereby promoting the generation of Circ-FNDC3B. Circ-FNDC3B is underexpressed in breast cancer and is characterized by a high metastatic risk. In addition, Circ-FNDC3B expression was reduced in breast cancer with larger tumor diameter, later clinical staging, and lymph node metastasis(LNM). The secondary structure of Circ-FNDC3B, specifically the 356-425 bp sequence, interacts with the biotin carboxylase domain of pyruvate carboxylase(PC), inhibiting the activity of PC. Low expression of Circ-FNDC3B enhances the activity of pyruvate carboxylase, thereby facilitating cell proliferation. The underlying mechanism involves the promotion of aspartate synthesis and the acceleration of the citrate - pyruvate cycle. This, in turn, promotes NADPH synthesis, thus alleviating the oxidative damage induced by reactive oxygen species (ROS). Furthermore, in human breast cancer organoids and a mouse model of lung metastasis, we have further validated that exogenous expression of circular RNA FNDC3B (Circ-FNDC3B) can inhibit the activity of pyruvate carboxylase (PC), thereby suppressing tumor proliferation and promoting tumor cell apoptosis. In general, upregulating the expression of circular Circ-FNDC3B can impede the progression of breast cancer. Implications: This study reveals significant heterogeneity of expression of circular RNAs commonly used to identify breast cancer metastasis, and confirms that circular RNAs affect the metabolic state of breast cancer through their binding proteins.

Uncontrolled cellular proliferation is a hallmark of cancer that is both driven by deregulation of the cell cycle, and fueled by metabolic reprogramming. Among the metabolic alterations detected, lipid metabolism is markedly upregulated to provide resources for proliferating cancer cells. Each cell cycle requires lipids for membrane synthesis, energy production, and cellular signaling, yet the mechanistic relationship linking the cell cycle to lipid metabolism in cancer remains incompletely understood. Recent advances in lipidomic technologies that enable comprehensive profiling of the cancer lipidome have provided new insights into the interconnections between these two pathways. This review describes how cell cycle regulators influence various aspects of lipid metabolism in models of cancer and the effect of cell cycle perturbation on cellular lipid profiles. We further describe lipid metabolic changes associated with response and resistance to cell cycle inhibitors in cancer and offer insight into how these findings may inform the development of clinical biomarkers and new therapeutic strategies.

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 multigene 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 enables 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 mechanisticically-informed and data-driven approaches.

Implications: CGPA is a streamlined, interactive platform for multicontext gene-centric prognostic analysis, simplifying biomarker discovery and validation for molecular and basic cancer scientists and bridging a critical gap in translational cancer research.