Deciphering Dormant Cells of Lung Adenocarcinoma: Prognostic Insights from O-glycosylation-Related Tumor Dormancy Genes Using Machine Learning.

Lung adenocarcinoma (LUAD) poses significant challenges due to its complex biological characteristics and high recurrence rate. The high recurrence rate of LUAD is closely associated with cellular dormancy, which enhances resistance to chemotherapy and evasion of immune cell destruction. Using single-cell RNA sequencing (scRNA-seq) data from LUAD patients, we categorized the cells into two subclusters: dormant and active cells. Utilizing high-density Weighted Gene Co-expression Network Analysis (hdWGCNA) and pseudo-time cell trajectory, aberrant expression of genes involved in protein O-glycosylation was detected in dormant cells, suggesting a crucial role for O-glycosylation in maintaining the dormant state. Intercellular communication analysis highlighted the interaction between fibroblasts and dormant cells, where the Insulin-like Growth Factor (IGF) signaling pathway regulated by O-glycosylation was crucial. By employing Gene Set Variation Analysis (GSVA) and machine learning, a risk score model was developed using hub genes, which showed high accuracy in determining LUAD prognosis. The model also demonstrated robust performance on the training dataset and excellent predictive capability, providing a reliable basis for predicting patient clinical outcomes. The group with a higher risk score exhibited a propensity for adverse outcomes in the tumor microenvironment (TME) and tumor mutational burden (TMB). Additionally, the 50% inhibitory concentration (IC50) values for chemotherapy exhibited significant variations among the different risk groups. In vitro experiments demonstrated that EFNB2, PTTG1IP, and TNFRSF11A were upregulated in dormant tumor cells, which also contributed greatly to the diagnosis of LUAD. In conclusion, this study highlighted the crucial role of O-glycosylation in the dormancy state of LUAD tumors and developed a predictive model for the prognosis of LUAD patients.

In Vitro and In Vivo Systems to Study Tumor Dormancy and the Transition to Overt Metastases Induced by the Fibrotic Milieu.

Metastatic breast cancer is a major cause of mortality among breast cancer patients (Sauer et al. Front Oncol: 11:659963, 2021). It may emerge years or even decades after the initial treatment of the primary tumor. This latency in the manifestation of the disease is attributed to the presence of early disseminated tumor cells (DTCs) that lay quiescent (dormant) for years until they emerge as clinically overt metastases. Given that to date we have no treatment to cure metastatic disease, it is vital to investigate ways to eradicate dormant DTCs and/or prevent their emergence to overt metastases. Here, we present a modified 3-dimensional in vitro system to model the in vivo growth characteristics of several tumor cell lines that exhibit either dormant behavior (D2.0R, MCF7) or transient dormant metastatic behavior (D2A1) at a metastatic secondary site. Additionally, we present an in vitro and complementary in vivo system to study the switch from dormancy to metastatic growth driven by a fibrotic-like milieu enriched with the deposition of type I collagen.

Clinical Tumor Dormancy.

This chapter summarizes clinical evidence on tumor dormancy, with a special focus on our research supporting the role of dormancy both in local and distant recurrence of breast cancer following mastectomy. Starting from these premises, we propose a model of neoplastic development that allows us to elucidate several relevant clinical phenomena, including the mammographic paradox, the significance of ipsilateral breast tumor recurrence after conservative surgery, and the effect of surgeries performed after the removal of the primary. We will discuss the biological implications of the dormancy-based model, which are at odds with Somatic Mutation Theory. We will then review new models, alternatives to the Somatic Mutation Theory, for cancer development, with special emphasis on the Dynamic System Theory and the originality of its conceptual approach. Finally, we will put particular emphasis on the view of cancer development as a tissue-level process. We believe that this will help harmonize the molecular biology research with the new conceptual approach and bridge the knowledge gap on dormancy between bench and bedside.

Modeling Tumor Cell Dormancy in an Ex Vivo Liver Metastatic Niche.

Despite decades of research into metastatic disease, our knowledge of the mechanisms governing dormancy are still limited. Unraveling the process will aid in developing effective therapies to either maintain or eliminate these dormant cells and thus prevent them from emerging into overt metastatic disease. To study the behavior of dormant tumor cells-mechanisms that promote, maintain, and disrupt this state-we utilize the Legacy LiverChip®, an all-human ex vivo hepatic microphysiological system. This complex, bioengineered system is able to recreate metastatic disease that is reflective of the human situation and is among only a handful of systems able to mimic spontaneous tumor cell dormancy. The dormant subpopulation reflects the defining traits of cellular dormancy-survival in a foreign microenvironment, chemoresistance, and reversible growth arrest. This microphysiological system has and continues to provide critical insights into the biology of dormant tumor cells. It also serves as an accessible tool to identify new therapeutic strategies targeting dormancy and concurrently evaluate the efficacy of therapeutic agents as well as their metabolism and dose-limiting toxicity.

Advances in the molecular regulation mechanism of tumor dormancy and its therapeutic strategy.

Tumor dormancy is a stage in the growth and development of malignant cells and is one of the biological characteristics of malignant cells. Complex transitions involving dormant tumor cells between quiescent and proliferative states pose challenges for tumor eradication. This paper explores the biological features and molecular mechanisms of tumor dormancy and highlights emerging therapies. The strategies discussed promise innovative clinical potential against malignant tumors. Understanding the mechanisms of dormancy can help provide valuable insights into the diagnosis and treatment of malignant tumors to advance the fight against this world problem.

Metabolic vulnerability of cancer stem cells and their niche.

Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.

Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles.

Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells in patients and mice. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor micro-RNAs, such as miR-99b-3p. Furthermore, we evaluated the effects of mechanical loading and treadmill exercise on the bone metastasis progression of NSCLC in mice. As expected, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

Dissemination of Circulating Tumor Cells in Breast and Prostate Cancer: Implications for Early Detection.

Burgeoning evidence suggests that circulating tumor cells (CTCs) may disseminate into blood vessels at an early stage, seeding metastases in various cancers such as breast and prostate cancer. Simultaneously, the early-stage CTCs that settle in metastatic sites [termed disseminated tumor cells (DTCs)] can enter dormancy, marking a potential source of late recurrence and therapy resistance. Thus, the presence of these early CTCs poses risks to patients but also holds potential benefits for early detection and treatment and opportunities for possibly curative interventions. This review delves into the role of early DTCs in driving latent metastasis within breast and prostate cancer, emphasizing the importance of early CTC detection in these diseases. We further explore the correlation between early CTC detection and poor prognoses, which contribute significantly to increased cancer mortality. Consequently, the detection of CTCs at an early stage emerges as a critical imperative for enhancing clinical diagnostics and allowing for early interventions.

Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies.

The period between "successful" treatment of localized breast cancer and the onset of distant metastasis can last many years, representing an unexploited window to eradicate disseminated disease and prevent metastases. We find that the source of recurrence-disseminated tumor cells (DTCs) -evade endogenous immunity directed against tumor neoantigens. Although DTCs downregulate major histocompatibility complex I, this does not preclude recognition by conventional T cells. Instead, the scarcity of interactions between two relatively rare populations-DTCs and endogenous antigen-specific T cells-underlies DTC persistence. This scarcity is overcome by any one of three immunotherapies that increase the number of tumor-specific T cells: T cell-based vaccination, or adoptive transfer of T cell receptor or chimeric antigen receptor T cells. Each approach achieves robust DTC elimination, motivating discovery of MHC-restricted and -unrestricted DTC antigens that can be targeted with T cell-based immunotherapies to eliminate the reservoir of metastasis-initiating cells in patients.

Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer.

Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer.

Autophagy induced by Helicobacter Pylori infection can lead to gastric cancer dormancy, metastasis, and recurrence: new insights.

According to the findings of recent research, Helicobacter Pylori (H. pylori) infection is not only the primary cause of gastric cancer (GC), but it is also linked to the spread and invasion of GC through a number of processes and factors that contribute to virulence. In this study, we discussed that H. pylori infection can increase autophagy in GC tumor cells, leading to poor prognosis in such patients. Until now, the main concerns have been focused on H. pylori's role in GC development. According to our hypothesis, however, H. pylori infection may also lead to GC dormancy, metastasis, and recurrence by stimulating autophagy. Therefore, understanding how H. pylori possess these processes through its virulence factors and various microRNAs can open new windows for providing new prevention and/or therapeutic approaches to combat GC dormancy, metastasis, and recurrence which can occur in GC patients with H. pylori infection with targeting autophagy and eradicating H. pylori infection.

Radiation-induced dormancy of intracerebral melanoma: endotoxin inflammation leads to both shortened tumor dormancy and long-term survival with localized senescence.

Radiation therapy (RT) treats approximately half of all cancers and most brain cancers. RT is variably effective at inducing a dormant tumor state i.e. the time between RT and clinical recurrence of tumor growth. Interventions that significantly lengthen tumor dormancy would improve long-term outcomes. Inflammation can promote the escape of experimental tumors from metastatic dormancy in the lung. Previously we showed intracerebral B16F10 melanoma dormancy varied with RT dose; 20.5 Gy induced dormancy lasted ~ 2 to 4 weeks-sufficient time to study escape from dormancy. Tumors were followed over time using bioluminescence. Surprisingly, some tumors in endotoxin-treated mice exited from dormancy slower; a large fraction of the mice survived more than 1-year. A cohort of mice also experienced an accelerated exit from dormancy and increased mortality indicating there might be variation within the tumor or inflammatory microenvironment that leads to both an early deleterious effect and a longer-term protective effect of inflammation. Some of the melanin containing cells at the site of the original tumor were positive for senescent markers p16, p21 and ßGal. Changes in some cytokine/chemokine levels in blood were also detected. Follow-up studies are needed to identify cytokines/chemokines or other mechanisms that promote long-term dormancy after RT.

Bibliometric Analysis of Global Research on Tumor Dormancy.

Tumor dormancy continues to be a research hotspot with numerous pressing problems that need to be solved. The goal of this study is to perform a bibliometric analysis of pertinent articles published in the twenty-first century. We concentrate on significant keywords, nations, authors, affiliations, journals, and literature in the field of tumor dormancy, which will help researchers to review the results that have been achieved and better understand the directions of future research. We retrieved research articles on tumor dormancy from the Web of Science Core Collection. This study made use of the visualization tools VOSviewer, CiteSpace, and Scimago Graphica, as visualization helps us to uncover the intrinsic connections between information. Research on tumor dormancy has been growing in the 21st century, especially from 2015 to the present. The United States is a leader in many aspects of this research area, such as in the number of publications, the number of partners, the most productive institutions, and the authors working in this field. Harvard University is the institution with the highest number of publications, and Aguirre-Ghiso, Julio A. is the author with the highest number of publications and citations. The keywords that emerged after 2017 were "early dissemination", "inhibition", "mechanism", "bone metastasis", and "promotion". We believe that research on tumor dormancy mechanisms and therapy has been, and will continue to be, a major area of interest. The exploration of the tumor dormancy microenvironment and immunotherapeutic treatments for tumor dormancy is likely to represent the most popular future research topics.

Autophagy and Breast Cancer: Connected in Growth, Progression, and Therapy.

Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to the development of multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted therapies, and cdk4/6 inhibitors. Immunotherapy is also being actively examined for some breast cancer subtypes. This overall positive outlook is marred by the development of resistance or reduced efficacy of the drug combinations, but the underlying mechanisms are somewhat unclear. It is interesting to note that cancer cells quickly adapt and evade most therapies by activating autophagy, a catabolic process designed to recycle damaged cellular components and provide energy. In this review, we discuss the role of autophagy and autophagy-associated proteins in breast cancer growth, drug sensitivity, tumor dormancy, stemness, and recurrence. We further explore how autophagy intersects and reduces the efficacy of endocrine therapies, targeted therapies, radiotherapy, chemotherapies as well as immunotherapy via modulating various intermediate proteins, miRs, and lncRNAs. Lastly, the potential application of autophagy inhibitors and bioactive molecules to improve the anticancer effects of drugs by circumventing the cytoprotective autophagy is discussed.

Could senescence phenotypes strike the balance to promote tumor dormancy?

After treatment and surgery, patient tumors can initially respond followed by a rapid relapse, or respond well and seemingly be cured, but then recur years or decades later. The state of surviving cancer cells during the long, undetected period is termed dormancy. By definition, the dormant tumor cells do not proliferate to create a mass that is detectable or symptomatic, but also never die. An intrinsic state and microenvironment that are inhospitable to the tumor would bias toward cell death and complete eradication, while conditions that favor the tumor would enable growth and relapse. In neither case would clinical dormancy be observed. Normal cells and tumor cells can enter a state of cellular senescence after stress such as that caused by cancer therapy. Senescence is characterized by a stable cell cycle arrest mediated by chromatin modifications that cause gene expression changes and a secretory phenotype involving many cytokines and chemokines. Senescent cell phenotypes have been shown to be both tumor promoting and tumor suppressive. The balance of these opposing forces presents an attractive model to explain tumor dormancy: phenotypes of stable arrest and immune suppression could promote survival, while reversible epigenetic programs combined with cytokines and growth factors that promote angiogenesis, survival, and proliferation could initiate the emergence from dormancy. In this review, we examine the phenotypes that have been characterized in different normal and cancer cells made senescent by various stresses and how these might explain the characteristics of tumor dormancy.

Establishment and Application of in vitro and in vivo Model of Disseminated Tumor Cells with Dormancy / 肿瘤防治研究

Postoperative asymptomatic patients with early cancer (lung cancer) have dormant disseminated tumor cells (DTCs) in their metastatic target organs, and the proliferation of these DTCs is the key link leading to clinical metastasis. The development of therapeutic agents to maintain DTCs dormant or eradicate dormant DTCs will prevent tumor metastasis and break through the bottleneck of improving the overall efficacy of treating malignant tumors. This paper reviews the methods of establishing in vitro and in vivo research models of DTCs with dormant characteristics to promote the understanding of dormant DTCs and improve the research and development efficiency of anti-tumor metastasis drugs.

Recent Insights into Mechanisms Governing Breast Cancer Dormancy / 肿瘤防治研究

Tumor dormancy refers to the status of disseminated cancer cells that remain in a viable yet not proliferating state for a prolonged period. Dormant cells will eventually "re-awake" resume their proliferation, and produce overt metastasis. The dormancy mechanism of cancer has attracted attention because of the close relationship between late recurrence and tumor dormancy. In this review, we illustrate the latest discoveries on the biological underpinnings of breast cancer dormancy and offer clinicians an overview of dormancy in breast cancer to guide them in the basic understanding of the complexity that underlies this process.

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy.

An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as "concomitant immunity" suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

Escape from breast tumor dormancy: The convergence of obesity and menopause.

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.