Oncogenesis最新文献

Bone-marrow mesenchymal stem cells (BM-MSCs) rely on glycolysis, yet their trafficked mitochondria benefit recipient cells’ bioenergetics in regenerative and cancerous settings, most relevant to BM-resident multiple myeloma (MM) cells. Fission/fusion dynamics regulate mitochondria function. Proteomics demonstrates excessive mitochondrial processes in BM-MSCs from MM patients compared to normal donors (ND). Thus, we aimed to characterize BM-MSCs (ND, MM) mitochondrial fitness, bioenergetics and dynamics with a focus on therapeutics. MM-MSCs displayed compromised mitochondria evidenced by decreased mitochondrial membrane potential (ΔΨm) and elevated proton leak. This was accompanied by stimulation of stress-coping mechanisms: spare respiratory capacity (SRC), mitochondrial fusion and UPR^mt. Interfering with BM-MSCs mitochondrial dynamics equilibrium demonstrated their significance to bioenergetics and fitness according to the source. While ND-MSCs depended on fission, reducing MM-MSCs fusion attenuated glycolysis, OXPHOS and mtROS. Interestingly, optimization of mtROS levels is central to ΔΨm preservation in MM-MSCs only. MM-MSCs also demonstrated STAT3 activation, which regulates their OXPHOS and SRC. Targeting MM-MSC’ SRC with Venetoclax diminished their pro-MM support and sensitized co-cultured MM cells to Bortezomib. Overall, MM-MSCs distinct mitochondrial bioenergetics are integral to their robustness. Repurposing Venetoclax as anti-SRC treatment in combination with conventional anti-MM drugs presents a potential selective way to target MM-MSCs conferred drug resistance.

Glioblastoma (GBM) is one of the most malignant primary brain tumors, and factors governing its progression are not fully characterized. Recent research suggests that the long non-coding RNA (lncRNA) HOTAIR and super-enhancers (SEs) contribute significantly to GBM progression. Here, we performed TCGA data analysis revealing that high HOTAIR expression in GBM is associated with poor prognosis. Conversely, HOTAIR knock-down (KD) decreased proliferation, colony formation, and invasion of GBM cells. Furthermore, RNA-seq analysis identified DEGs in GBM cells related to cell growth and adhesion. Using an integrated approach, we also identify MEST as a HOTAIR-associated SE target gene. Intriguingly, MEST suppression in GBM cells phenocopied HOTAIR KD, as evidenced by reduced cell proliferation and invasion, whereas MEST overexpression counteracted effects of HOTAIR depletion. Moreover, 3 C technique-based PCR confirmed reduced interaction between HOTAIR-associated SEs and target genes after HOTAIR KD. This study reveals a novel regulatory mechanism governing GBM, offering promising directions for clinical interventions.

Up to 30% of acute myeloid leukemia (AML) patients face unfavorable outcomes due to the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Although FLT3 inhibitors show encouraging outcomes in treatment, they fail to eliminate leukemia stem cells, the origin of persistent and resistant lesions. Exploration of the mechanism in FLT3-ITD⁺ AML maintenance and chemoresistance is crucial for the development of novel therapeutic approaches. The manifestation of pluripotency transcription factors (TFs) and their link to clinical outcomes have been documented in various tumors. This study investigates the correlation between core pluripotency TF and treatment in AML. We discovered that FLT3 inhibition induced upregulation of OCT4 and NANOG in FLT3-ITD⁺ AML cells. Subsequently, we demonstrated that downregulation of OCT4 or NANOG inhibited cell growth, promoted apoptosis, and induced G0/G1 cell cycle phase arrest in FLT3-ITD⁺ AML cells. Knockdown of OCT and NANOG inhibited tumor growth in a mouse tumor model. OCT4 promotes the malignant biological behavior of FLT3-ITD⁺ AML by enhancing the abnormal FLT3 signaling pathway through transcriptional activation of NANOG. Importantly, downregulation of OCT4 or NANOG increased responsiveness to FLT3-tyrosine kinase inhibitor (TKI) (Gilteritinib), implying that OCT4 and NANOG may contribute to TKI resistance in FLT3-ITD⁺ AML. Our study verifies the involvement of OCT4/NANOG in regulating TKI sensitivity and targeting them may improve the cytotoxicity of FLT3-TKIs in FLT3-ITD⁺ AML.

Cancer-associated fibroblast (CAF) recruitment and activation within the tumor microenvironment (TME) are increasingly acknowledged as drivers of oral squamous cell carcinoma (OSCC) tumor growth and metastasis. Therefore, the mechanisms underlying tumor cell and fibroblast crosstalk warrant further investigation. We discovered that ectopic interferon-stimulated gene 15 (ISG15) expression, which is a promising and novel oncoprotein biomarker elevated in a variety of cancers, enhanced OSCC growth and elevated collagen and α-smooth muscle actin (α-SMA) expression in ISG15-expressing tumors. Analysis of immunohistochemistry revealed high ISG15 expression in human oral tissues correlated with high expression of α-SMA and fibroblast activation protein (FAP). Fibroblast migration and recruitment by ISG15-expressing OSCC cells were confirmed by in vitro and in vivo experiments. Exogenous ISG15 induced fibroblast migration, morphological changes, and vimentin expression. Enrichment of glycolysis pathway genes, as well as increased glycolysis-related gene expression, glucose uptake, and lactate production were observed in ISG15-treated fibroblasts. Lactate release and fibroblast migration were blocked by a competitive inhibitor of glucose metabolism. Furthermore, the knockdown of integrin αL (ITGAL)/CD11a, a subunit of ISG15 receptor lymphocyte functional-associated antigen-1 (LFA-1), in immortalized fibroblasts diminished extracellular ISG15-mediated glycolysis and migration. Our findings suggest that ISG15 derived from OSCC cells interacts with fibroblasts through the LFA-1 receptor, leading to glycolytic reprogramming and promotion of fibroblast migration into the TME.

The prevention and precise treatment of early-stage lung adenocarcinoma (LUAD) characterized by small nodules (stage IA) remains a significant challenge for clinicians, which is due largely to the limited understanding of the oncogenic mechanisms spanning from preneoplasia to invasive adenocarcinoma. Our study highlights the pivotal role of cancer cells exhibiting high expression of centromere protein F (CENPF), driven by TP53 mutations, which become increasingly prevalent during the transition from preneoplasia to invasive LUAD. Biologically, cancer cells (CENPF+) exhibited robust proliferative and stem-like capabilities, thereby propelling the malignant progression of early-stage LUAD. Clinically, autoantibodies against CENPF in the serum and elevated cancer cells (CENPF+) in tissue correlated positively with the progression of early-stage LUAD, especially those in stage IA. Our findings suggest that cancer cells (CENPF+) play a central role in orchestrating the malignant evolution of LUAD and hold potential as a novel biomarker for early-stage detection and management of the disease.

Expression of stromal antigen 2 (STAG2), a member of the cohesin complex, is associated with aggressive tumor characteristics and worse clinical outcomes in muscle invasive bladder cancer (MIBC) patients. The mechanism by which STAG2 acts in a pro-oncogenic manner in bladder cancer remains unknown. Due to this elusive role of STAG2, targetable vulnerabilities based on STAG2 expression have not yet been identified. In the current study, we sought to uncover therapeutic vulnerabilities of muscle invasive bladder cancer cells based on the expression of STAG2. Using CRISPR-Cas9, we generated isogenic STAG2 wild-type (WT) and knock out (KO) cell lines and treated each cell line with a panel of 312 anti-cancer compounds. We identified 100 total drug hits and found that STAG2 KO sensitized cells to treatment with PLK1 inhibitor rigosertib, whereas STAG2 KO protected cells from treatment with MEK inhibitor TAK-733 and PI3K inhibitor PI-103. After querying drug sensitivity data of over 4500 drugs in 24 bladder cancer cell lines from the DepMap database, we found that cells with less STAG2 mRNA expression are more sensitive to ATR and CHK inhibition. In dose-response studies, STAG2 KO cells are more sensitive to the ATR inhibitor berzosertib, whereas STAG2 WT cells are more sensitive to PI3K inhibitor PI-103. These results, in combination with RNA-seq analysis of STAG2-regulated genes, suggest a novel role of STAG2 in regulating PI3K signaling in bladder cancer cells. Finally, synergy experiments revealed that berzosertib exhibits significant synergistic cytotoxicity in combination with cisplatin against MIBC cells. Altogether, our study presents evidence that berzosertib, PI-103, and the combination of berzosertib with cisplatin may be novel opportunities to investigate as precision medicine approaches for MIBC patients based on STAG2 tumor expression.

Pancreatic carcinoma (PC) is the sixth leading cause of cancer death in both sexes in 2022, responsible for almost 5% of all cancer deaths worldwide; it is characterized by a poor prognosis since most patients present with an unresectable and metastatic tumor. To date, the decreasing trend in mortality rates related to the most common cancers has contributed to making pancreatic cancer a serious public health problem. In the last few years, scientific research has led to many advances in diagnostic approaches, perioperative management, radiotherapy techniques, and systemic therapies for advanced disease, but only with modest incremental progress in PC patient outcomes. Most of the causes of this high mortality are, unfortunately, late diagnosis and an important therapeutic resistance; for this reason, the most recent high-throughput proteomics technologies focus on the identification of novel biomarkers and molecular profiling to generate new insights in the study of PC, to improve diagnosis and prognosis and to monitor the therapies progress. In this work, we present and discuss the integration of results from different revised studies on protein biomarkers in a global proteomic meta-analysis to understand which path to pursue scientific research. In particular, cancer signaling, inflammatory response, and cell migration and signaling have emerged as the main pathways described in PC, as well as scavenging of free radicals and metabolic alteration concurrently highlighted new research insights on this disease. Interestingly, from the study of upstream regulators, some were found to be shared by collecting data relating to both biological fluid and tissue biomarkers, side by side: specifically, TNF, LPS, p38-MAPK, AGT, miR-323-5p, and miR-34a-5p. By integrating many biological components with their interactions and environmental relationships, it's possible to achieve an in-depth description of the pathological condition in PC and define correlations between concomitant symptoms and tumor genesis and progression. In conclusion, our work may represent a strategy to combine the results from different studies on various biological samples in a more comprehensive way.

Notch signaling is altered in breast cancer. Recent studies highlighted both tumor-suppressive and oncogenic roles for Notch in this tissue. The function of Jagged1, the most highly expressed Notch ligand in the mammary gland, is not well defined. Here we report that deletion of Jagged1 in the mammary epithelium of virgin mice led to expansion of the mammary stem cell (MaSC) compartment and defective luminal differentiation associated with decreased expression of the progesterone receptor (PR). In contrast, deletion of Jagged1 in alveolar cells of pregnant mice had no effect on alveolar and lactogenic differentiation or post-lactational involution. Interestingly, deletion of Jagged1 promoted mouse mammary tumor formation from luminal cells but suppressed them from basal cells, associated with downregulation of Notch target genes Hey1 and Hey2, respectively. In agreement with mouse experiments, high expression of JAG1 and HEY1 are associated with better overall survival among patients with luminal tumors, whereas high expression of JAG1 and HEY2 are both associated with worse overall survival in basal subtype of human breast cancer. These results identified Jagged1 as an important regulator of mammary epithelial hierarchy and revealed differential roles of Jagged1-mediated Notch signaling in different subtypes of breast cancer arising from distinct cell types.

Diffuse large B-cell lymphoma (DLBCL) is characterized by its aggressive nature and resistance to standard chemotherapy, necessitating the development of new therapeutic approaches. The emergence of natural products and their derivatives has notably influenced cancer treatment, making morusinol, a medicine-derived monomer, a promising candidate. Here, we showed that morusinol exerted antitumor effects on DLBCL in vitro by inducing apoptosis and cell cycle arrest. Impressively, morusinol treatment exhibited potent tumor growth inhibition in vivo, proving both well-tolerated and safe in mouse models. Moreover, our investigation identified FUT8, a fucosyltransferase, as a potential target for morusinol. FUT8's role as an oncogene in DLBCL and its correlation with poor survival further underscored its significance. Furthermore, our screening efforts involving clinical and preclinical drugs unveiled a compelling synergistic effect between chidamide and morusinol. Additionally, morusinol's ability to hinder M2-like polarization of tumor-associated macrophages suggested its potential in immune response modulation within DLBCL. Collectively, morusinol showcased substantial promise as an anti-tumor agent for potential clinical application in DLBCL management, potentially augmenting established therapeutic strategies. Moreover, our findings offered promising prospects for natural products to effectively leverage its therapeutic advantages. Working model: The role of Morusinol in treating DLBCL.

Glioblastoma stem cells (GSCs) are pivotal in the recurrence and drug resistance of glioblastoma multiforme (GBM). However, precision therapeutic and diagnostic markers for GSCs have not been fully established. Here, using bioinformatics and experimental analysis, we identified P4HB, a protein disulfide isomerase, as a serum marker that maintains stemness in GSCs through the Wnt/β-catenin signaling pathway. Transcriptional silencing of P4HB induces apoptosis and diminishes stem cell-like characteristics in GSCs. Treatments with the chemical CCF624 or the China National Medical Products Administration (NMPA)-approved securinine significantly prolonged survival in patient-derived xenograft mouse models, underscoring P4HB's potential as a therapeutic target and presenting an expedited path to clinical application through drug repurposing. Additionally, elevated P4HB levels in patient serum were found to correlate with disease progression, underscoring its utility as a biomarker and its promise for precision medicine.