Immune evasion: An imperative and consequence of MYC deregulation.

MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene-specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription-replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell-autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard-wired to the biology of the MYC protein family. We show why the cell-autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy.

SLC7A11: the Achilles heel of tumor?

The non-natriuretic-dependent glutamate/cystine inverse transporter-system Xc- is composed of two protein subunits, SLC7A11 and SLC3A2, with SLC7A11 serving as the primary functional component responsible for cystine uptake and glutathione biosynthesis. SLC7A11 is implicated in tumor development through its regulation of redox homeostasis, amino acid metabolism, modulation of immune function, and induction of programmed cell death, among other processes relevant to tumorigenesis. In this paper, we summarize the structure and biological functions of SLC7A11, and discuss its potential role in tumor therapy, which provides a new direction for precision and personalized treatment of tumors.

The YY1-CPT1C signaling axis modulates the proliferation and metabolism of pancreatic tumor cells under hypoxia.

Carnitine palmitoyltransferase 1C (CPT1C) is an enzyme that regulates tumor cell proliferation and metabolism by modulating mitochondrial function and lipid metabolism. Hypoxia, commonly observed in solid tumors, promotes the proliferation and progression of pancreatic cancer by regulating the metabolic reprogramming of tumor cells. So far, the metabolic regulation of hypoxic tumor cells by CPT1C and the upstream mechanisms of CPT1C remain poorly understood. Yin Yang 1 (YY1) is a crucial oncogene for pancreatic tumorigenesis and acts as a transcription factor that is involved in multiple metabolic processes. This study aimed to elucidate the relationship between YY1 and CPT1C under hypoxic conditions and explore their roles in hypoxia-induced proliferation and metabolic alterations of tumor cells. The results showed enhancements in the proliferation and metabolism of PANC-1 cells under hypoxia, as evidenced by increased cell growth, cellular ATP levels, up-regulation of mitochondrial membrane potential, and decreased lipid content. Interestingly, knockdown of YY1 or CPT1C inhibited hypoxia-induced rapid cell proliferation and vigorous cell metabolism. Importantly, for the first time, we reported that YY1 directly activated the transcription of CPT1C and clarified that CPT1C was a novel target gene of YY1. Moreover, the YY1 and CPT1C were found to synergistically regulate the proliferation and metabolism of hypoxic cells through transfection with YY1 siRNA to CRISPR/Cas9-CPT1C knockout PANC-1 cells. Taken together, these results indicated that the YY1-CPT1C axis could be a new target for the intervention of pancreatic cancer proliferation and metabolism.

Thyroid hormone enhances efficacy of cisplatin in lung cancer patients via down-regulating GLUT1 expression and reversing the Warburg effect.

Cisplatin (CDDP) is a standard non-small cell lung cancer (NSCLC) chemotherapy, but its efficacy is hampered by resistance, partly due to the Warburg effect. This study investigates how thyroid hormones enhance the Warburg effect, increasing sensitivity to cisplatin in lung cancer. Clinical data from advanced NSCLC patients were analyzed based on thyroid hormone levels, categorizing patients into high and low groups. Cellular experiments involved Control, 10uM CDDP, 10uM CDDP + 0.1uM T3, and 10uM CDDP + 0.1uM T4 categories. Parameters were measured in A549 and PC9 lung cancer cells, including proliferation, apoptosis, mitochondrial membrane potential, ROS production, glycolysis enzyme activity, lactic acid level, and ATP content. Gene and protein expressions were assessed using qPCR and Western Blot. Analysis revealed higher FT3 levels correlated with prolonged progression-free survival before chemotherapy (median PFS: high FT3 group = 12.67 months, low FT3 group = 7.03 months, p = 0.01). Cellular experiments demonstrated that thyroid hormones increase lung cancer cell sensitivity to cisplatin, inhibiting proliferation and enhancing efficacy. The mechanism involves thyroid hormones and cisplatin jointly down-regulating MSI1/AKT/GLUT1 expression, reducing lactic acid and glycolysis. This Warburg effect reversal boosts ATP levels, elevates ROS, and decreases MMP, enhancing cisplatin effectiveness in A549 and PC9 cells. In conclusion, elevated free T3 levels in advanced NSCLC patients correlate with prolonged progression-free survival under cisplatin chemotherapy. Cellular experiments reveal that thyroid hormones enhance lung cancer cell sensitivity to cisplatin by reversing the Warburg effect, providing a mechanistic basis for improved therapeutic outcomes.

Merging Metabolic Modeling and Imaging for Screening Therapeutic Targets in Colorectal Cancer.

Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved high-throughput computational screening to investigate the effects of enzyme perturbations predicted by a computational model of CRC metabolism to understand system-wide effects efficiently. Our results highlighted hexokinase (HK) as one of the crucial targets, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF conditioned media exhibited increased sensitivity to HK inhibition. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk.

The emerging roles of glutamine amidotransferases in metabolism and immune defense.

Glutamine amidotransferases (GATs) catalyze the synthesis of nucleotides, amino acids, glycoproteins and an enzyme cofactor, thus serving as key metabolic enzymes for cell proliferation. Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is a multifunctional enzyme of the GAT family and catalyzes the first three steps of the de novo pyrimidine synthesis. Following our findings that cellular GATs are involved in immune evasion during herpesvirus infection, we discovered that CAD reprograms cellular metabolism to fuel aerobic glycolysis and nucleotide synthesis via deamidating RelA. Deamidated RelA activates the expression of key glycolytic enzymes, rather than that of the inflammatory NF-κB-responsive genes. As such, cancer cells prime RelA for deamidation via up-regulating CAD activity or accumulating RelA mutations. Interestingly, the recently emerged SARS-CoV-2 also activates CAD to couple evasion of inflammatory response to activated nucleotide synthesis. A small molecule inhibitor of CAD depletes nucleotide supply and boosts antiviral inflammatory response, thus greatly reducing SARS-CoV-2 replication. Additionally, we also found that CTP synthase 1 (CTPS1) deamidates interferon (IFN) regulatory factor 3 (IRF3) to mute IFN induction. Our previous studies have implicated phosphoribosyl formylglycinamidine synthase (PFAS) and phosphoribosyl pyrophosphate amidotransferase (PPAT) in deamidating retinoic acid-inducible gene I (RIG-I) and evading dsRNA-induced innate immune defense in herpesvirus infection. Overall, these studies have uncovered an unconventional enzymatic activity of cellular GATs in metabolism and immune defense, offering a molecular link intimately coupling these fundamental biological processes.

Tumor metabolism in pheochromocytomas: clinical and therapeutic implications.

Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors.

Purinosomes involved in the regulation of tumor metabolism: current progress and potential application targets.

The core of tumor cell metabolism is the management of energy metabolism due to the extremely high energy requirements of tumor cells. The purine nucleotide synthesis pathway in cells uses the purinosomes as an essential spatial structural complex. In addition to serving a crucial regulatory role in the emergence and growth of tumors, it contributes to the synthesis and metabolism of purine nucleotides. The significance of purine metabolism in tumor cells is initially addressed in this current article. The role of purinosomes as prospective therapeutic targets is then reviewed, along with a list of the signaling pathways that play in the regulation of tumor metabolism. A thorough comprehension of the function of purinosomes in the control of tumor metabolism can generate fresh suggestions for the creation of innovative cancer treatment methods.

One-day examination of triple nuclear medicine imaging and application in evaluating transarterial embolization.

A diagnosis based on multiple nuclear medicine imaging (NMI) was more comprehensive in approaching the nature of pathological changes. In this research, a method to realize triple NMIs within one day was developed based on the reasonable arrangements of 68Ga-RGD PET/CT specialized on neovascularization, 99mTc-HL-91 SPECT/CT specialized on hypoxia and 18F-FDG PET/CT specialized on tumor metabolism. Feasibility was verified in evaluating the therapeutic effects of transarterial embolization (TAE) performed on rabbit models with VX2 tumor. Radiation dosimetry was carried out to record the radiation exposure from multiple injections of radiopharmaceuticals. In results, the one-day examination of triple NMIs manifested the diversity of the postoperative histological changes, including the local neovascularization induced by embolization, hypoxic state of embolized tissues, and suppression of tumor metabolism. More importantly, radiation dosage from radiopharmaceuticals was limited below 5.70 ± 0.90 mSv. In conclusion, the strong timeliness and complementarity of one-day examination of triple nuclear medicine imaging made it clinically operative and worthy of popularizing. There was flexibility in combining distinct NMIs according to the clinical demands, so as to provide comprehensive information for diagnosis.

Autophagy in glioblastoma: A mechanistic perspective.

Glioblastoma (GBM) is one of the most lethal malignancies in humans. Even after surgical resection and aggressive radio- or chemotherapies, patients with GBM can survive for less than 14 months. Extreme inter-tumor and intra-tumor heterogeneity of GBM poses a challenge for resolving recalcitrant GBM pathophysiology. GBM tumor microenvironment (TME) exhibits diverse heterogeneity in cellular composition and processes contributing to tumor progression and therapeutic resistance. Autophagy is such a cellular process; that demonstrates a cell-specific and TME context-dependent role in GBM progression, leading to either the promotion or suppression of GBM progression. Autophagy can regulate GBM cell function directly via regulation of survival, migration, and invasion, or indirectly by affecting GBM TME composition such as immune cell population, tumor metabolism, and glioma stem cells. This review comprehensively investigates the role of autophagy in GBM pathophysiology.

Breast cancer clinical outcomes and tumor immune microenvironment: cross-dialogue of multiple epigenetic modification profiles.

The discovery of RNA methylation alterations associated with cancer holds promise for their utilization as potential biomarkers in cancer diagnosis, prognosis, and prediction. RNA methylation has been found to impact the immunological microenvironment of tumors, but the specific role of methylation-related genes (MRGs), particularly in breast cancer (BC), the most common cancer among women globally, within the tumor microenvironment remains unknown. In this study, we obtained data from TCGA and GEO databases to investigate the expression patterns of MRGs in both genomic and transcriptional domains in BC. By analyzing the data, we identified two distinct genetic groupings that were correlated with clinicopathological characteristics, prognosis, degree of TME cell infiltration, and other abnormalities in MRGs among patients. Subsequently, an MRG model was developed to predict overall survival (OS) and its accuracy was evaluated in BC patients. Additionally, a highly precise nomogram was created to enhance the practical usability of the MRG model. In low-risk groups, we observed lower TBM values and higher TIDE scores. We further explored how MRGs influence a patient's prognosis, clinically significant characteristics, response to therapy, and the TME. These risk signatures have the potential to improve treatment strategies for BC patients and could be applied in future clinical settings. Moreover, they may also be utilized to determine prognosis and biological features in these patients.

Histology-Based Radiomics for [18F]FDG PET Identifies Tissue Heterogeneity in Pancreatic Cancer.

Radiomics features can reveal hidden patterns in a tumor but usually lack an underlying biologic rationale. In this work, we aimed to investigate whether there is a correlation between radiomics features extracted from [18F]FDG PET images and histologic expression patterns of a glycolytic marker, monocarboxylate transporter-4 (MCT4), in pancreatic cancer. Methods: A cohort of pancreatic ductal adenocarcinoma patients (n = 29) for whom both tumor cross sections and [18F]FDG PET/CT scans were available was used to develop an [18F]FDG PET radiomics signature. By using immunohistochemistry for MCT4, we computed density maps of MCT4 expression and extracted pathomics features. Cluster analysis identified 2 subgroups with distinct MCT4 expression patterns. From corresponding [18F]FDG PET scans, radiomics features that associate with the predefined MCT4 subgroups were identified. Results: Complex heat map visualization showed that the MCT4-high/heterogeneous subgroup was correlating with a higher MCT4 expression level and local variation. This pattern linked to a specific [18F]FDG PET signature, characterized by a higher SUVmean and SUVmax and second-order radiomics features, correlating with local variation. This MCT4-based [18F]FDG PET signature of 7 radiomics features demonstrated prognostic value in an independent cohort of pancreatic cancer patients (n = 71) and identified patients with worse survival. Conclusion: Our cross-modal pipeline allows the development of PET scan signatures based on immunohistochemical analysis of markers of a particular biologic feature, here demonstrated on pancreatic cancer using intratumoral MCT4 expression levels to select [18F]FDG PET radiomics features. This study demonstrated the potential of radiomics scores to noninvasively capture intratumoral marker heterogeneity and identify a subset of pancreatic ductal adenocarcinoma patients with a poor prognosis.

Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite.

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.

Crosstalk between metabolism and cell death in tumorigenesis.

It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.

The Tumor Microenvironment: Signal Transduction.

In the challenging tumor microenvironment (TME), tumors coexist with diverse stromal cell types. During tumor progression and metastasis, a reciprocal interaction occurs between cancer cells and their environment. These interactions involve ongoing and evolving paracrine and proximal signaling. Intrinsic signal transduction in tumors drives processes such as malignant transformation, epithelial-mesenchymal transition, immune evasion, and tumor cell metastasis. In addition, cancer cells embedded in the tumor microenvironment undergo metabolic reprogramming. Their metabolites, serving as signaling molecules, engage in metabolic communication with diverse matrix components. These metabolites act as direct regulators of carcinogenic pathways, thereby activating signaling cascades that contribute to cancer progression. Hence, gaining insights into the intrinsic signal transduction of tumors and the signaling communication between tumor cells and various matrix components within the tumor microenvironment may reveal novel therapeutic targets. In this review, we initially examine the development of the tumor microenvironment. Subsequently, we delineate the oncogenic signaling pathways within tumor cells and elucidate the reciprocal communication between these pathways and the tumor microenvironment. Finally, we give an overview of the effect of signal transduction within the tumor microenvironment on tumor metabolism and tumor immunity.

Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment.

Recently, it has been recognized that physical abnormalities (e.g. elevated solid stress, elevated interstitial fluid pressure, increased stiffness) are associated with tumor progression and development. Additionally, these mechanical forces originating from tumor cell environment through mechanotransduction pathways can affect metabolism. On the other hand, mitochondria are well-known as bioenergetic, biosynthetic, and signaling organelles crucial for sensing stress and facilitating cellular adaptation to the environment and physical stimuli. Disruptions in mitochondrial dynamics and function have been found to play a role in the initiation and advancement of cancer. Consequently, it is logical to hypothesize that mitochondria dynamics subjected to physical cues may play a pivotal role in mediating tumorigenesis. Recently mitochondrial biogenesis and turnover, fission and fusion dynamics was linked to mechanotransduction in cancer. However, how cancer cell mechanics and mitochondria functions are connected, still remain poorly understood. Here, we discuss recent studies that link mechanical stimuli exerted by the tumor cell environment and mitochondria dynamics and functions. This interplay between mechanics and mitochondria functions may shed light on how mitochondria regulate tumorigenesis.

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.

Targeting the Warburg Effect in Cancer: Where Do We Stand?

The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.

Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.

Natural Killer (NK) cells are a top contender in the development of adoptive cell therapies for cancer due to their diverse antitumor functions and ability to restrict their activation against nonmalignant cells. Despite their success in hematologic malignancies, NK cell-based therapies have been limited in the context of solid tumors. Tumor cells undergo various metabolic adaptations to sustain the immense energy demands that are needed to support their rapid and uncontrolled proliferation. As a result, the tumor microenvironment (TME) is depleted of nutrients needed to fuel immune cell activity and contains several immunosuppressive metabolites that hinder NK cell antitumor functions. Further, we now know that NK cell metabolic status is a main determining factor of their effector functions. Hence, the ability of NK cells to withstand and adapt to these metabolically hostile conditions is imperative for effective and sustained antitumor activity in the TME. With this in mind, we review the consequences of metabolic hostility in the TME on NK cell metabolism and function. We also discuss tumor-like metabolic programs in NK cell induced by STAT3-mediated expansion that adapt NK cells to thrive in the TME. Finally, we examine how other approaches can be applied to enhance NK cell metabolism in tumors.