Experimental Hematology & Oncology最新文献

Liver pre-metastatic niches (PMN) formation is a pivotal process in colorectal cancer liver metastasis (CLM). Phosphatase of regenerating liver-3 (PRL-3) has been demonstrated as a key factor in promoting CRC progression (e.g., therapeutic resistance and metastasis), but its role in liver PMN formation remains unknown. Using mouse models and CRC patient samples, we herein reveal that high PRL-3 expression in CRC cells could enhance the recruitment of myeloid-derived suppressor cells (MDSCs) into the liver and impair the hepatic infiltration of CD8⁺ T cells, thereby promoting the liver PMN formation and CLM. Mechanistically, high PRL-3 expression could activate the Src/STAT3 signaling pathway in CRC cells and thus up-regulate integrin αvβ5 (ITGαvβ5) expression in their secreted exosomes, which could specifically target F4/80⁺ macrophages in the liver to activate the P38/STAT1 signaling pathway. With this activation of P38/STAT1 pathway, the secretion of C-X-C motif chemokine ligand 12 (CXCL12) from F4/80⁺ macrophages is significantly improved, which could enhance the recruitment of MDSCs into the liver and impair the hepatic infiltration of CD8⁺ T cells, ultimately leading to the liver PMN formation and CLM. Taken together, our findings not only uncover the important role of PRL-3 in CLM via promoting the liver PMN formation, but also provide the evidence for the treatment of CLM by targeting PRL-3.

PTEN deficiency is frequently observed in various cancers, including triple-negative breast cancer. However, PTEN loss-of-function mutations are not directly druggable, necessitating a synthetic lethality approach for treating PTEN-deficient tumors. Utilizing combinatorial CRISPR screening, we identified ICMT (isoprenylcysteine carboxylmethyltransferase) loss as synthetic lethal with PTEN deficiency. Genetic or pharmacological inhibition of ICMT effectively reversed cellular transformation induced by PTEN loss. Mechanistically, ICMT loss disrupts the positive feedback loop involving PIP3-PIP3-dependent guanine nucleotide exchange factor (GEF)-Rac1-PI3K by increased physical association of Rac1 and RhoGDI, inhibiting Rac1 activity and stability. Disruption of this feedback loop attenuates epithelial-mesenchymal transition and reduces the cancer stem cell population. Additionally, ICMT loss leads to the accumulation of aggregated proteins, which activates the unfolded protein response (UPR) signaling, ultimately resulting in cell death. Cysmethynil, an ICMT inhibitor, effectively suppresses PTEN-mutant cancer growth in xenograft models. Collectively, our study establishes ICMT as a promising therapeutic target for treating PTEN-mutant cancers.

Background: Tetrahydromagnolol (THM) is a compound isolated from Magnolia officinalis with unique chemical structure and composition. However, its anticancer effect of THM and the underlying molecular mechanisms remain unclear.

Method: Firstly, the anticancer effects of THM on different cancer cell lines in vitro were investigated. Subsequently, the antitumor activity of THM was further evaluated in vivo and in vitro using colorectal and lung cancer models. This assessment involved the effects of THM on cell viability, apoptosis, proliferation, cell cycle progression, and tumor growth inhibition. In addition, the anticancer molecular mechanisms of THM were determined by RNA sequencing, western blot, immunohistochemistry, immunofluorescence, CETSA, and SPR. Meanwhile, the effects of THM on organelles were evaluated by measuring endoplasmic reticulum stress, mitochondrial membrane potential damage, reactive oxygen species (ROS), and calcium ion concentration. Finally, the efficacy of THM in combination with conventional anticancer drugs for colorectal cancer treatment was evaluated in vivo.

Results: The results showed that THM had a significant anticancer activity in colorectal cancer and lung cancer both in vitro and in vivo. THM significantly inhibited cell proliferation and induced PANoptosis-like cell death through GSDME mediated pyroptosis, CASP3 mediated apoptosis, and MLKL mediated necroptosis. In addition, the anticancer potential of THM was also related to elevation of endoplasmic reticulum stress, mitochondrial membrane potential destruction, and increase of ROS and intracellular calcium concentration. Mechanically, we found that THM could directly bind to triplet motif-containing 38 (TRIM38) and induced its upregulation at mRNA and protein levels. Importantly, knockdown of TRIM38 remarkably rescued the anticancer effects of THM and PANoptosis induced by THM treatment, suggesting that TRIM38 played a key role in mediating the antitumor activity of THM. In addition, THM showed significant synergistic therapeutic effects when used in combination with conventional anticancer strategies (Cetuximab, FOLFOX, and FOLFIRI regimens) for colorectal cancer treatment.

Conclusion: Our data suggest that THM exerts its anticancer potential by inducing TRIM38-dependent PANoptosis and it also has synergistic antitumor effects in combination with conventional anticancer strategies. THM will be a promising candidate drug used alone or in combination with other anticancer regimens for cancer treatment.

Background: Outcomes for patients with esophageal squamous cell carcinoma (ESCC) remain poor, partly due to treatment resistance, particularly to DNA-damaging therapies. Poly(ADP‑ribose) polymerase 1 (PARP1) plays a critical role in repairing single‑strand DNA breaks (SSBs). Unrepaired SSBs can be converted into double‑strand breaks (DSBs) during DNA replication, potentially leading to cell death. Genomic amplification of the distal portion of chromosome 3q (3q26-q29) is a frequent copy‑number alteration in ESCC, which harbors genes encoding several oncoproteins. However, whether long noncoding RNAs (lncRNAs) from this region contribute to ESCC pathogenesis and treatment resistance remains poorly understood.

Methods: In situ hybridization and qPCR were used to assess RNA expression. Protein PARylation was evaluated by immunoprecipitation followed by Western blotting. Cellular phenotypes were quantified using the cell counting kit-8, Annexin V/Propidium iodide staining, and clonogenic assays. DNA damage was monitored by immunofluorescence staining for phosphorylated histone H2AX (γH2AX) and p53-binding protein 1 (53BP1) and by comet assays. RNA-protein interactions were assessed through RNA pulldown coupled with mass spectrometry and RNA immunoprecipitation. Chromatin fractionation and detergent pre-extraction immunofluorescence were conducted to examine PARP1 chromatin association. ESCC growth and responses to treatments were evaluated using xenograft models.

Results: The lncRNA LINC00885, hereafter referred to as PARylator, was the most upregulated lncRNA encoded within the 3q26-q29 amplicon in ESCC. PARylator was predominantly nuclear and interacted with PARP1. Knockdown of PARylator increased γH2AX and 53BP1 foci and comet tail moment, triggered apoptosis, reduced clonogenicity, sensitized ESCC cells to cisplatin and ionizing radiation. In vivo, PARylator knockdown impaired tumor growth and increased cisplatin sensitivity in ESCC xenografts. Mechanistically, PARylator promoted PARP1 recruitment to chromatin and catalytic activation, thereby increasing PARP1 auto-PARylation and enhancing the PARylation of X-ray repair cross-complementing 1 (XRCC1). PARylator was further upregulated in response to DNA damage.

Conclusions: The DNA damage-responsive, 3q26-q29 amplicon-encoded lncRNA PARylator promotes PARP1‑mediated PARylation and SSB repair, thereby limiting DSB accumulation and supporting ESCC cell survival and resistance to DNA-damaging therapies. Targeting PARylator, alone or in combination with DNA-damaging agents, may represent a novel avenue for ESCC treatment.

Patients with multiple myeloma bearing a deletion of chromosome 17p (del(17p)), mutation of TP53, or both have poorer prognosis compared to patients without these aberrations. We investigated the activity and mechanism of melflufen (melphalan flufenamide) in myeloma models with wild type TP53 (TP53wt) and complete TP53 deletion (TP53^-/-) and assessed the efficacy of melflufen in patients with del(17p) and/or TP53 mutation. Ex vivo data from myeloma plasma cells (PC) showed comparable activity of melflufen in del(17p), TP53^-/-, and TP53wt samples. scRNAseq data demonstrated that melflufen sensitive PCs had lower expression of p53 target genes and higher expression of genes associated with DNA damage repair and cell cycle checkpoints. Irrespective of TP53 status, melflufen induced apoptosis, DNA damage, and mitochondrial dysfunction, while only in TP53^-/- cells, it led to changes in expression of cell cycle checkpoint and apoptosis genes. Post-hoc analysis of the OCEAN trial melflufen-treated del(17p) patient population also demonstrated favorable progression free survival compared to pomalidomide-treated cohort. Our insights into the molecular mechanisms of melflufen activity in TP53^-/- myeloma support its clinical efficacy and application in the del(17p) and TP53^-/- patient population.Trial registration NCT03151811, registration 2017-05-09.

Rearranged T and B-cell receptor loci serve as critical clonal markers for studying adaptive immune system functioning during normal immune response and abnormal expansion in lymphoid malignancies. Analyses of both complete and partial TCR/BCR gene rearrangements provide valuable insights into the clonal proliferation of malignant T and B lymphocytes. Our earlier work identified novel partial rearrangements between two D (diversity) genes in the human TRB locus in normal T cells from peripheral blood and thymus. In this study, we demonstrate the presence of these novel rearrangements in leukemic T cells, explore their properties for clonality assessment and potential use in minimal residual disease (MRD) monitoring in acute lymphoblastic leukemia, and lay the foundation for further clinical validation.

Hepatocellular carcinoma (HCC) is a major liver malignancy and a leading cause of cancer-related mortality worldwide. Given its rising incidence and poor prognosis, there is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop novel targeted therapies. In this study, we identify MAML1 as a key contributor to HCC development. Elevated MAML1 expression strongly correlated with disease severity, whereas its knockdown suppressed HCC progression. Functionally, MAML1 promoted tumor malignancy by regulating STAT3 activity. Mechanistically, MAML1 interacted with STAT3 and enhanced its acetylation in a p300-dependent manner. Inhibition of STAT3 with a specific inhibitor attenuated MAML1-driven HCC progression. Furthermore, signaling pathway analyses revealed that YAP is the principal transcription factor regulating MAML1 expression by directly binding its promoter. Importantly, depletion of MAML1 diminished YAP-induced HCC malignancy and STAT3 activation, suggesting that YAP, MAML1, and STAT3 form a coordinated signaling axis that drives HCC progression. Collectively, these findings uncover a novel MAML1-centered signaling pathway in HCC and provide a compelling rationale for the development of MAML1-targeted clinical strategies for disease management.

While CAR-T cell therapy has been very successful for treating B cell malignancies, and more recently multiple myeloma, achieving clinical success for acute myeloid leukemia (AML) remains a significant challenge. The examination of current single-antigen targeting CAR-T cell studies for AML illustrates the challenges faced by this therapy: efficacy limitations arise from the heterogeneity of the disease, which often results in antigen escape and subsequent circumvention of single-antigen targeting CAR-T cells, while safety limitations are mainly due to undesired hematological toxicity stemming from the absence of an antigen specifically expressed on AML tumor cells and not on normal hematopoietic cells. This study offers a comprehensive analysis of the most relevant AML surface antigenic markers -CD123, CD33, ADGRE2, CLL-1, TIM-3, CD70, among others- along with their expression patterns across key cell types, including leukemic blasts, leukemic stem cells, hematopoietic stem cells and progenitors, adult blood cells, and other tissues. Additionally, a variety of strategies for developing CAR-T therapies with improved efficacy and specificity are explored, with dual-antigen targeting CAR-T cell therapies emerging as the most promising approach to overcome the major hurdles observed in single-antigen targeting CAR-T cell therapies. Overall, this review identifies dual-antigen targeting as a therapy holding great prospects in the search of an effective and safe therapeutic approach for AML patients.

The development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment represents a significant challenge to targeted therapies for lung cancer. To explore the feasibility of epigenetic therapy in overcoming resistance, an epigenetic drug library was screened, identifying Remodelin as a potent enhancer of EGFR-TKI sensitivity in non-small cell lung cancer (NSCLC) cells. We demonstrated that the cytidine acetyltransferase NAT10 was overexpressed in NSCLC tissues and was associated with poor patient prognosis. NAT10 knockdown inhibited proliferation, increased apoptosis, and enhanced sensitivity to EGFR-TKIs both in vitro and in vivo. Mechanistically, NAT10 promoted EGFR-TKI resistance in NSCLC by remodeling fatty acid metabolism. Specifically, NAT10 was found to promote ac4C modification of fatty acid transport protein 4 (FATP4) and carnitine palmitoyltransferase 1 A (CPT1A) mRNAs, leading to increased stability and expression of these genes. Furthermore, p300-mediated H3K27ac acetylation was found to be a critical upstream regulator of NAT10 transcription. In vivo, mouse xenograft models confirmed that Remodelin significantly enhanced the antitumor efficacy of gefitinib. These findings suggest the potential of NAT10 as a therapeutic target to overcome EGFR-TKI resistance and improve treatment outcomes in patients with NSCLC.

Background: Malignant ascites (MA) is one of the major complications in advanced epithelial cancer patients and is associated with poor prognosis, poor quality of life, and severe symptoms. No efficient medicine is available for treating MA worldwide. Only paracentesis is recommended by the guidelines in most countries, but with limited efficacy and a short control time. Thus, novel treatments are needed to control MA.

Methods: An anti-EpCAM × anti-CD3 bispecific antibody, M701, was constructed as a T-cell engager to eliminate tumor cells in the peritoneal cavity. A phase II study was performed to evaluate the efficacy and safety of the intraperitoneal (IP) infusion of M701 in advanced epithelial tumor patients with moderate-to-large-scale MA. In this study, 84 patients were enrolled, with 43 in the M701 group receiving paracentesis and IP M701 infusion and 41 in the control group receiving paracentesis alone.

Results: The primary endpoint, median puncture-free survival (PuFS), was 75 days in the M701 group and 25 days in the control group, with a significant difference (p = 0.0065). Subgroup analysis indicated that different types of cancer, including gastric, colorectal, and ovarian cancers, all benefited from the M701 infusion. Patients with higher relative lymphocyte counts (≥ 13%) at baseline received better effects. Compared to patients in the control group, the overall survival (OS) of patients in the M701 group was certain extended (mOS 110 days vs. 76 days, p = 0.1443, HR = 0.68). The 6-month survival rates were 33.3% and 12.1% in the two groups, respectively. No additional serious adverse events (SAEs) were detected in the M701 group. The most frequent treatment-related adverse events were anemia and low white blood cell count, which were manageable. M701 infusions did not cause a greater risk than paracentesis alone in the control arm, while all patients were administered systemic treatment.

Conclusion: When treated with M701, patients with MA had significantly longer puncture intervals and a trend of extended survival time. The results were encouraging for patients with MA. A phase III clinical trial of M701 aimed at further validation is ongoing.