Molecular Cancer Research最新文献

Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating the development of diverse treatment options to improve patient outcomes. The tumor microenvironment (TME) plays a critical role in determining the efficacy of these different therapies, yet the reciprocal impact of treatment on the TME, particularly the tumor immune microenvironment (TIME), remains incompletely understood. This review investigates the different effects of cancer therapies-chemotherapy, targeted therapy, immunotherapy, and radiotherapy-on immune cells within the TIME and associated extracellular vesicles (EV). The broader impact on the TME belies a complex and nuanced tumor response. These treatments have been shown to have an impact on the function of various immune cells, influencing their activity to either promote or block tumor growth. Importantly, this review also considers how these therapies play an indirect role in modulating the TIME by influencing the release and contents of EVs, highlighting the significant role that EVs play in intercellular communication within the TIME. By analyzing recent findings, this review aims to provide a comprehensive understanding of how different cancer therapies reshape the TIME. Understanding these dynamic relationships can help pave the way for optimizing existing treatments, developing new therapies, and enhancing patient outcomes.

Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multiomic analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of extracellular matrix remodeling in SRC lesions compared with unaffected adjacent gastric epithelium. Single-cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, and KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin reexpression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared with SRC lesions.

Implications: The marked differences in the genomic and transcriptomic profiles of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.

As a vital form of posttranscriptional modification, RNA N6-methyladenosine (m6A) methylation dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. In this study, we have found that methyltransferase-like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on farnesyltransferase, subunit alpha (FNTA) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA-binding protein 1 recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a cross-talk between METTL3-mediated RNA methylation and FNTA-mediated protein modification, which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity.

Implications: Targeting the METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.

Protein homeostasis is critical to the survival of multiple myeloma cells. Although this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity of multiple myeloma cells to the translation inhibitor omacetaxine. We hypothesized that understanding how multiple myeloma becomes resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S multiple myeloma cell lines and compared them with parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC50 > 100 nmol/L, compared with parental sensitivity of 24 to 54 nmol/L. As omacetaxine inhibits protein synthesis, we performed both RNA sequencing and ribosome profiling to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing a terminal oligopyrimidine sequence in their 5' untranslated region were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of terminal oligopyrimidine motif-containing mRNAs. Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. The combination was synergistic in omacetaxine-naïve multiple myeloma cell lines, and a combination effect was observed in vivo. Primary multiple myeloma cells from patient samples were also sensitive to the combination. These results provide a rational approach for omacetaxine-based combination therapy in patients with multiple myeloma, which have historically shown better responses to multiagent regimens.

Implications: Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma.

New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity. TRAIL analogs or agonistic antibodies targeting these receptors are available but have not yet received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may activate TRAIL receptors as a monotherapy or potentiate the efficacy of TRAIL analogs and agonistic antibodies. Previously described disulfide bond-disrupting agents activate DR5 by altering its disulfide bonding through inhibition of protein disulfide isomerases ERp44, AGR2, and PDIA1. Work presented in this article extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of caspase 8/caspase 3-mediated proapoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy and as research tools. Importantly, other endoplasmic reticulum (ER) stressors, including thapsigargin and tunicamycin, also alter DR5 disulfide bonding in various cancer cell lines, and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the integrated stress response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands.

Implications: Extreme ER stress triggers triage of transmembrane receptor production, whereby mitogenic receptors are downregulated and death receptors are simultaneously elevated.

Tumor-associated macrophages (TAM) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression-free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their protumorigenic role. Blocking SPP1 in the RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment and increased CD8+ T-cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition in advanced prostate cancer.

Implications: This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.

Multiple lines of correlative evidence support a role for angel homolog 2 (ANGEL2), a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and survival of patients with cancer. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. In this study, we demonstrate that loss of ANGEL2 leads to a substantial decrease in the key tumor-suppressor protein tumor protein p53 (TP53). We show that ANGEL2 directly interacts with eukaryotic translation initiation factor 4E (EIF4E), the rate-limiting protein in cap-dependent translation. This interaction abrogates the ability of the TP53 translation repressor RNA-binding motif protein 38 to interact with EIF4E, thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased two-dimensional and three-dimensional spheroid cell growth and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven-amino-acid peptide derived from ANGEL2, rescued wild-type (WT) TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RNA-binding motif protein 38 complex to enhance WT TP53 translation, and furthermore, the Pep7 peptide may be explored as a therapeutic strategy for cancers that harbor WT TP53 expression.

Implications: Loss of ANGEL2 contributes to decreased WT TP53 translation promoting doxorubicin resistance, which can be rescued via an ANGEL2-derived peptide.

Small cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. In this study, we show that kinase suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony-forming ability of tumor-propagating cells in vitro and their tumor-initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor-propagating cell function and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of SCLC-A tumors and a potential subtype-specific therapeutic target.

Implications: Manipulation of the molecular scaffold KSR2 in SCLC-A cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.

Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of empty spiracles homeobox 2 (EMX2) in patients with RCC and revealed a significant reduction of EMX2 expression, correlating with a poor prognosis in patients with RCC. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA sequencing and chromatin immunoprecipitation sequencing analyses, we have identified cell adhesion molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates caspase-3-dependent apoptosis in attached RCC cells. Furthermore, the EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by the EMX2-CADM1 axis promote RCC cell death and suppress its growth and invasion, providing potential intervention strategies for combating RCC.

Implications: The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in RCC, which could lead to more effective treatment strategies for this aggressive malignancy.

An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells and acts by controlling the pluripotency-differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development.

Implications: SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.