Molecular Cancer Research最新文献

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.

A high therapeutic index, defined as potent inhibition of oncogenic signaling in tumor cells with minimal effects on normal cells, is critical for effective cancer therapies. Recent advances have introduced diverse RAS-targeting inhibitors, including mutant-specific inhibitors such as KRAS G12C and KRAS G12D, as well as paralog- and state-selective inhibitors. Non-mutant-specific RAS inhibition can be achieved by: (i) guanine nucleotide exchange-OFF inhibitors that indirectly inactivate RAS by targeting SHP2 or SOS1, (ii) KRAS-OFF inhibitors that spare NRAS and HRAS, and (iii) active-state RAS(ON) inhibitors that directly block binding of effector RAF. However, the signaling inhibition index (SII)-the differential suppression of oncogenic signaling between RAS-mutant and normal cells-remains poorly defined for these approaches. We evaluated the SII for state- and paralog-selective RAS inhibitors across diverse RAS-mutant and RAS-wild-type models. Guanine nucleotide exchange-OFF inhibitors exhibited neutral or negative values, with reduced MAPK suppression in KRAS G12X cells compared with wild-type cells. KRAS G13D models, especially with NF1 loss, showed low sensitivity. SHP2 plus MEK inhibition resulted in low selectivity, and RAS Q61X models were resistant due to MEK inhibitor-induced NRAS reactivation and altered SHP2 conformations. KRAS-OFF inhibitors demonstrated higher selectivity, whereas active- state RAS(ON) inhibitors showed broader activity but narrow selectivity. Sensitivity to mutant-specific inhibitors largely overlapped with sensitivity to state-selective agents, suggesting that most RAS-mutant tumors will respond poorly to any currently available RAS inhibitor.

Implications: Determining the SII can inform the design and clinical application of RAS-targeted therapies to improve tumor selectivity and therapeutic outcomes.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Temozolomide (TMZ) is the most widely used chemotherapeutic agent and can significantly improve patient survival rates. However, numerous patients develop TMZ resistance, leading to limited therapeutic benefits. Therefore, it is crucial to investigate the mechanisms of TMZ resistance in patients with GBM and identify the sensitizing targets of TMZ to improve its clinical efficacy. In this study, we demonstrated that acylphosphatase 2 (ACYP2) was involved in regulating the sensitivity of GBM to TMZ. ACYP2 knockdown significantly reduced the IC50 values of TMZ in GBM cells, whereas overexpression of ACYP2 increased their IC50 values. The combination of ACYP2 knockdown and TMZ treatment not only inhibited the malignant behavior of GBM cells in vitro but also slowed the progression of intracranial GBM in mice. Additionally, comet tail and γ-H2AX staining assays showed that ACYP2 knockdown enhanced the TMZ-induced DNA damage. Mechanistically, ACYP2 upregulates the transcription factor c-Myc to promote the transcription of its downstream target PARP1, an important regulatory molecule for DNA damage repair, ultimately inducing TMZ resistance in GBM cells. Thus, this study demonstrated that ACYP2 is a potential therapeutic target for TMZ-resistant patients with GBM.

Implications: The ACYP2-driven c-Myc/PARP1 signaling axis defines a critical pathway driving TMZ resistance and represents a translationally actionable target for therapeutic intervention in GBM.

Prostate cancer ranges from indolent to rapidly progressive. An elevated cell proliferation index portends poor outcomes, yet the molecular alterations essential for increased cell proliferation remain ill-defined. Gain of MYC combined with biallelic PTEN loss predicts prostate cancer mortality. Prior studies have shown that combined MYC overexpression and Pten loss, driven by the Hoxb13 locus, results in prostatic intraepithelial neoplastic (PIN) lesions that progress to metastatic disease (BMPC mice). Yet, single gene alterations in these mice result only in PIN lesions. In this study, we performed transcriptomic profiling of PIN lesions from each of the three genotypes. Whereas MYC alone resulted in increases in genes related to cell-cycle regulation/cell division, combined MYC and Pten loss led to a further and more consistent increase and a synergistic cell-cycle progression. Increased ribosome biogenesis/translation is required for cell proliferation. Whereas MYC alone increased 45S rRNA and most components of the translation machinery, these were more strongly induced in BMPC mice. Surprisingly, Pten loss alone resulted in a downregulation of translation machinery genes, which could explain the absence of biallelic PTEN loss in human PIN lesions and early carcinomas. Some MYC targets were increased only after Pten loss, indicating Pten loss increases MYC activity.

Implications: Increased cell cycle and translational machinery gene induction may explain the synergy between MYC and PTEN loss for increasing prostate cancer cell proliferation and disease aggressiveness. These results provide further support for the therapeutic targeting of translation in prostate cancer.

Although kidney cancer arises from a variety of nephron cells with diverse characteristics and develops intra-tumor heterogeneity, a model to elucidate these complexities is incompletely developed. Here, we report a genetically engineered human iPS cell-derived kidney organoid (HKO) model, which may recapitulate an early stage of renal tumorigenesis. When we overexpressed VCL-ALK fusion gene, a renal oncogene, in HKO, tubular cells proliferated and this proliferation was sustained under long-term culture or hypoxic conditions. In addition, the proliferating tubular cells migrated into the renal parenchyma of host mice upon transplantation. The deconvolution analysis and immunohistochemistry revealed that proliferating tubular cells could be arrested at an immature tubular progenitor stage with increased expressions of LHX1 and JAG1, critical regulators of nephrogenesis. Our HKO model advances our understanding of renal tumorigenesis in the context of the trajectory of nephron development. Implications: Dysregulated nephron developmental machinery leads to aberrant cell proliferations of immature renal tubules.

Temozolomide (TMZ) resistance is an urgent problem in the treatment of glioma. circNEIL3 is related with the malignant progression of glioma. Nevertheless, the function of circNEIL3 in TMZ resistance is still unclear. In this study, we found that circNEIL3 is over-expressed in glioma tissues and cells, and is related with TMZ resistance. Cell experiments and mouse experiments have shown that inhibiting the expression of circular NEIL3 can enhance the sensitivity of glioma cells to TMZ. The RIP and other molecular experiments demonstrated that circNEIL3 and the RNA-binding protein U2 small nuclear RNA auxiliary factor 2 (U2AF2) interact with each other and partially colocalize in cells. SPI1 was highly expressed in glioma, more significantly in TMZ-resistant tissues, and correlated with circNEIL3 expression. Furthermore, we discovered that U2AF2 interacts with SPI1 mRNA as well, and circNEIL3 and U2AF2 together regulate the expression and mRNA stability of SPI1. More importantly, SPI1 silencing inhibited the malignant progression of cells, and partially reversed the effects of circNEIL3 on glioma cell proliferation and apoptosis. In conclusion, circNEIL3 stabilizes SPI1 mRNA expression by binding to U2AF2, thereby promoting glioma progression and temozolomide resistance. Implications: Our findings offer a new mechanistic insights into gliomas drug resistance, and targeting the circNEIL3/U2AF2/SPI1 axis represents a promising approach to counteract TMZ resistance in gliomas.

Neutrophils are one of the most important immune cells in the tumor microenvironment, and they affect the immunosuppression status by directly supporting the tumor progression or indirectly impairing T cell antitumor response. Although recent evidence indicates that neutrophils determine the success of tumor immunotherapy, how to activate the innate immune system antitumor response still lags out. Here, we provide evidence that the methotrexate packaged tumor cell-derived microparticles (MTX-MP) activate neutrophil antitumor response by directly releasing tumor cytotoxic microparticles, increasing tumor-infiltrated CD8+ T cells, and promoting CD8+ T cell antitumor response. Strikingly, mitochondrial-lysosomal membrane contacts mediate NADH translocation to lysosomal compartments. Within lysosomes, ENOX2 catalyzes NADH oxidation to generate lysosomal reactive oxygen species (ROS), which induce Ca2+ efflux via lysosomal channels. This calcium surge triggers neutrophil degranulation, thereby promoting cytotoxic microparticle release. By performing the combination of MTX-MP-activated neutrophils and OT-1 CD8+ T cells transfer, we found that the long-term survival rate improved in OVA-expressing Lewis lung carcinoma (LLC-OVA) models. Implications: Our findings revealed a new way by which activated-neutrophils release microparticles to kill tumor cells and provided a potential combinatorial therapeutic strategy for tumor immunotherapy.

While the androgen receptor (AR) is canonically known for its role in the prostate and testis, AR signaling exerts broad immunomodulatory effects through direct and indirect signaling in multiple immune cell compartments and contributes significantly to sex differences in autoimmunity, infection, and cancer. Mouse model perturbations of androgen signaling through castration, testicular feminization, and cell type-specific AR knockout have provided important insights into cell-intrinsic and -extrinsic mechanisms by which AR signaling affects innate and adaptive immunity. However, the precise molecular underpinnings of these effects remain largely unknown. Moreover, despite convincing epidemiological and correlative observations that highlight the importance of AR signaling in human immune function, it remains unclear how reliably findings in mice will translate to humans. A better understanding of how to augment immune function through androgen signaling modulation could have significant clinical relevance for the treatment of cancer, as well as other disease states involving immune dysregulation. In this review, we discuss the current evidence for the functional effects of AR signaling within the major immune cell compartments of the innate and adaptive immune systems. We also review ongoing clinical efforts that modify AR signaling for the purpose of enhancing antitumor immunity.

The driver genes of wild-type gastrointestinal stromal tumors (WT-GISTs), particularly quadruple WT-GIST (qWT-GIST), remain unclear. In this study, we collected 119 WT-GISTs from two cohorts and analyzed their clinicopathological and genomic features, particularly for qWT-GISTs. Next-generation sequencing (NGS) revealed several fusion genes and gene mutations, such as ARID1B, SETD2, and PLCG2, in qWT-GISTs. Further integrated KEGG pathway analysis revealed significantly enriched signaling pathways in qWT-GISTs, including the HIF-1. For qWT-GISTs, large tumors or a high mitotic index prompted a shorter RFS, and a high mitotic index or involvement of the HIF-1 pathway prompted a shorter OS; however, neither RFS nor OS was prolonged by postoperative adjuvant therapy. In addition, compared with SDH-deficient GISTs, qWT-GISTs were less frequently found in the stomach and less frequently presented as high mitotic index; compared with RAS-related GISTs, qWT-GISTs were more frequently found in the stomach. Stratified analyses showed, in patients with low recurrence risk, qWT-GISTs had better RFS than SDH-deficient GISTs. In patients with high recurrence risk or with postoperative adjuvant therapy, qWT-GISTs presented worse OS than SDH-deficient GISTs. In summary, qWT-GISTs exhibited unique clinicopathological characteristics and outcomes compared to SDH-deficient and RAS-related GISTs, suggesting that they should be managed using different treatment and follow-up strategies, especially stratified management. Considering the rarity and heterogeneity of WT-GISTs, a regulatory detection procedure should be established for WT-GISTs, including NGS for qWT-GISTs, to identify the molecular mechanisms and potential therapeutic targets. Implications: WT-GISTs are heterogenous tumors which should be managed using different treatments and follow-up strategies.