Molecular Cancer Research最新文献

One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the β-adrenergic receptor agonist isoproterenol rapidly stimulate cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation at Ser133 in human PDAC cells. Exposure to the nonselective β-adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551, blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA, whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D. Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet that promotes early PDAC development were subjected to social isolation stress. We show that social isolation stress induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia) in KC mice subjected to an obesogenic high fat, calorie diet. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.

Recent evidence indicates that a high-fat diet can promote tumor development, especially colorectal cancer, by influencing the microbiota. Regulatory circular RNA (circRNA) plays an important role in modulating host-microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a high-fat diet modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein, referred to as circ_0126925) in colorectal cancer. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumors from limited branched-chain amino acid (BCAA) interference by improving the metabolism of BCAAs in colorectal cancer. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of colorectal cancer by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host-microbe interactions in colorectal cancer. Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome-related pathology in humans.

Our research aims to understand the adaptive-ergo potentially metastatic-responses of prostate cancer to changing microenvironments. Emerging evidence implicates a role of the polyaneuploid cancer cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study revealed that PACC presence in patient prostate tumors at the time of radical prostatectomy was predictive of future metastasis. To test for a causative relationship between PACC state biology and metastasis in prostate cancer, we leveraged a novel method designed for flow cytometric detection of circulating tumor cells (CTC) and disseminated tumor cells (DTC) from animal models. This approach provides both quantitative and qualitative information about the number and PACC status of recovered CTCs and DTCs. Specifically, we applied this approach to the analysis of subcutaneous, caudal artery, and intracardiac murine models. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. Furthermore, in vivo colonization assays proved that PACC populations can regain proliferative capacity at metastatic sites. Additional in vitro analyses revealed a PACC-specific partial epithelial-to-mesenchymal transition phenotype and a prometastatic secretory profile, together providing preliminary evidence of prometastatic mechanisms specific to the PACC state. Implications: Considering that many anticancer agents induce the PACC state, our data position the increased metastatic competency of PACC state cells as an important unforeseen ramification of neoadjuvant regimens, which may help explain clinical correlations between chemotherapy and metastatic progression.

Extravasation is a key step in tumor metastasis. Epstein‒Barr virus plays a crucial role in nasopharyngeal carcinoma (NPC) metastasis. However, the functions and molecular mechanisms of Epstein‒Barr virus during tumor cell extravasation remain unclear. Here, we showed that the expression of pyroptosis-associated proteins is greater in the endothelial cells of metastatic NPC tissues than in those of nontumor tissues exosomes derived from NPC cells promoted endothelial cell pyroptosis, vascular permeability, and tumor cell extravasation. Moreover, we found that BART2-5p is abundant in serum exosomes from patients with NPC metastasis and in NPC cells and that it regulates endothelial cell pyroptosis in premetastatic organs via MRE11A. Exosomes containing a BART2-5p inhibitor and AAV-MRE11A attenuated endothelial cell pyroptosis and tumor metastasis. Moreover, in the endothelial cells of metastatic tissues from patients with NPC, the BART2-5p level was positively associated with pyroptosis-related protein expression. Collectively, our findings suggest that exosomal BART2-5p is involved in premetastatic niche formation, identifying secreted BART2-5p as a potential therapeutic target for NPC metastasis. Implications: The finding that secreted BART2-5p is involved in premetastatic niche formation may aid the development of a potential therapeutic target for NPC metastasis.

Cancer remains one of the most formidable challenges in the medical field in this century, largely because of its poorly understood pathogenesis. Fortunately, recent advancements in the understanding of cancer pathogenesis have helped identify more therapeutic targets for improved treatment outcomes. The WNT signaling pathways are highly conserved cascades that participate in diverse physiologic processes, such as embryonic development, tissue homeostasis, and tissue regeneration. Ferroptosis, a unique iron-dependent form of cell death that is distinct from apoptosis, is driven by lipid peroxidation and excessive reactive oxygen species production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate cross-talk, plays crucial roles in cancer progression and therapeutic resistance, indicating their potential as targets for cancer therapies. This review provides a comprehensive overview of the current understanding of the cross-talk between WNT signaling pathways and ferroptosis in the pathogenesis and progression of cancer, with a specific focus on the regulatory role of the canonical WNT cascade in cancer-related ferroptosis. In addition, we discuss the pharmacologic mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors and ferroptosis inducers with current therapies represents a promising therapeutic strategy for personalized cancer treatment.

TIPE is a protein highly expressed in various cancers that promotes ferroptosis in colorectal cancer cells. Ferroptosis is a nonapoptotic cell death caused by lipid peroxidation, and microsomal glutathione transferase 1 (MGST1) is a critical enzyme that resists lipid peroxidation. This study explored how TIPE regulates MGST1 expression to inhibit ferroptosis and promote colorectal cancer proliferation. TIPE was highly expressed in colorectal cancer tissues and positively correlated with the proliferation of human colorectal cancer cells. We measured levels of reactive oxygen species and lipid reactive oxygen species in colorectal cancer cells with differential expression of TIPE and detected ferroptosis using transmission electron microscopy. Bioinformatics analysis revealed a positive correlation of expression patterns between TIPE and MGST1 in colorectal cancer. TIPE regulated the expression of MGST1 by activating the phosphorylation of ERK1/2. Coimmunoprecipitation revealed binding between MGST1 and ALOX5. This binding inhibited the phosphorylation of ALOX5, inhibiting ferroptosis and promoting the proliferation of colorectal cancer cells. A tumor formation experiment in nude mice supported our findings that TIPE regulates the proliferation of colorectal cancer by regulating ferroptosis. Implications: TIPE inhibits colorectal cancer ferroptosis via an MGST1-ALOX5 interaction to promote colorectal cancer proliferation. These findings suggest future colorectal cancer treatment strategies.

Colorectal cancer tumors start as polyps on the inner lining of the colorectum, in which they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select colorectal cancer lines that harbored an oncogenic mutation in the Kirsten rat sarcoma virus (KRAS) gene. In this study, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in colorectal cancer. Peristalsis enriched cancer stem cell marker Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in KRAS mutant lines in a Wnt ligand-independent manner. Conversely, LGR5 enrichment in wild-type KRAS lines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicity in vivo. Differences in mechanotransduction were apparent via unbiased gene set enrichment analysis, in which many unique pathways were enriched in wild-type versus mutant lines. Peristalsis also triggered β-catenin nuclear localization independent of Wnt ligands, particularly in KRAS mutant lines. The involvement of KRAS was validated via gain and loss of function strategies. Peristalsis-induced β-catenin activation and LGR5 enrichment depended on the activation of the MEK/ERK cascade. Taken together, our results demonstrated that oncogenic KRAS mutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain independent of other cooperating signals.

Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic cholangiocarcinoma (iCCA) or extrahepatic cholangiocarcinoma (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared with other common cancers. Utilizing previously published transcriptome data, our reanalysis has revealed that CCA has one of the highest relative levels of NK cells, a potent cytotoxic immune cell, compared with other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in patients with eCCA. Our subsequent investigation revealed that although iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK coculture, eCCA was markedly more sensitive. Moreover, although both iCCA and eCCA dysregulated key NK-activating receptors, eCCA coculture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed a modulation of multiple immune and nonimmune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.

Approximately 70% of oropharyngeal squamous carcinomas (OPSCC) are associated with human papillomavirus (HPV). Although patients with HPV-positive (HPV+) tumors generally have better outcomes than those with HPV-negative tumors, a subset of HPV+ positive patients do have poor outcomes. Our previous work suggested that tumors with integrated virus exhibit significantly greater genome-wide genomic instability than those with only episomal viral genomes, and patients with HPV+ OPSCC with episomal viral genomes had better outcomes. To explore the causal relation between viral integration and genomic instability, we have examined the time course of viral integration and genetic instability in tonsillar keratinocytes transformed with HPV16. HPV-infected human tonsil keratinocyte cell lines were continuously passaged, and every fifth passage, some cells were retained for genomic analysis. Whole-genome sequencing and optical genomic mapping confirmed that virus integrated in five of six cell lines while remaining episomal in the sixth. In all lines, genome instability occurred during early passages but essentially ceased following viral integration; however, it continued to occur in later passages in the episomal line. To test tumorigenicity of the cell lines, cells were injected subcutaneously into the flanks of nude mice. A cell line with the integrated virus induced tumors following injection in the nude mouse whereas that with the episomal virus did not. Implications: Genomic instability in HPV OPSCC tumors is not the result of viral integration but likely promotes integration. Moreover, transformants with episomal virus seem to be less tumorigenic than those with integrated virus.

Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. Because RMS resembles skeletal muscle precursor cells, differentiation-inducing therapy has been proposed for patients with advanced disease. In RAS-mutant PAX fusion-negative RMS (FN-RMS) preclinical models, MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival. However, the response is short-lived. A better understanding of the molecular mechanisms regulating FN-RMS differentiation could improve differentiation therapy. In this study, we identified a role in FN-RMS differentiation for ASAP1, an ADP ribosylation factor (ARF) GTPase-activating protein (GAP) with both proinvasive and tumor-suppressor functions. We found that ASAP1 knockdown inhibited differentiation in FN-RMS cells. Interestingly, knockdown of the GTPases ARF1 or ARF5, targets of ASAP1 GAP activity, also blocked differentiation of FN-RMS. We discovered that loss of ARF pathway components blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation and inactivation of WW domain-containing transcriptional regulator 1 (WWTR1; TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1, regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation, which inhibits MEKi-induced differentiation. Finally, MEKi-induced differentiation was rescued by dual knockdown of ASAP1 and WWTR1. This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.