LncRNAs as Targetable Nodes of Oncogenic Networks Underlying Cancer Progression and Therapy Resistance

Simple SummaryNeutrophils are a type of white blood cell that also play a role in cancer. They have been shown to influence various aspects of the disease, including resistance to therapy. The role of neutrophils in cancer is now known to involve the extrusion of their DNA in a process called NETosis. The resulting protein-covered DNA webs are called neutrophil extracellular traps (NETs), which have been shown to interact with cancer cells. This interaction is now thought to drive resistance to various cancer therapies, including chemotherapy, immunotherapy, and radiation therapy. The evidence now suggests that NETs may be central facilitators of therapy resistance, bringing cancer cells into proximity with various proteins and factors, and driving multiple mechanisms concurrently. This paper will therefore provide an overview of current evidence implicating NETs in cancer therapy resistance and potential clinical applications.Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety of cancer therapies. Recently, the role of neutrophils in cancer progression and therapy resistance has been further complicated with the discovery of neutrophil extracellular traps (NETs). NETs are web-like structures of chromatin decorated with a variety of microbicidal proteins. They are released by neutrophils in a process called NETosis. NET-dependent mechanisms of cancer pathology are beginning to be appreciated, particularly with respect to tumor response to chemo-, immuno-, and radiation therapy. Several studies support the functional role of NETs in cancer therapy resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, the epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms, among others. Given this, new and promising data suggests NETs provide a microenvironment conducive to limited therapeutic response across a variety of neoplasms. As such, this paper aims to give a comprehensive overview of evidence on NETs in cancer therapy resistance with a focus on clinical applicability.

Therapy resistance of metastatic tumor cells poses a major limitation to the cure of cancer. Aside from cell-intrinsic processes, the tumor microenvironment is a contributor to this problem. Senescent cells can originate from healthy cells that accumulate irreparable damage. Senescent cells cease to divide, but chronically secrete a wide range of factors that permanently alter their environment. As such, they are thought to impair tissue function and, when part of a tumor microenvironment, they are thought to accelerate tumor progression, metastazation and therapy resistance. Today, I will discuss how we identified that therapy-surviving cancer cells can develop a stem-like state, which is, at least partially, driven by exogenous signals from senescent cells. In addition, I will show how therapy-surviving cancer cells can develop a senescence-like state of their own, including an associated pro-inflammatory secretory phenotype. Given the importance of cancer stemness in therapy resistance, both senescent stromal cells and senescence-like cancer cells pose exciting candidates for therapeutic removal. When designing therapies for elimination of, we ran into a problem, which is that there is no such thing as (just) senescence. Instead, there are distinct subtypes, which are not merely caused by noise. I will show how we investigate these subtypes of senescence and how this is important for their targeted elimination. More specifically, I will highlight interaction between the damage-associated proteins FOXO4 and p53 as a pivot in the viability of a damaged type of senescence, which we call now call “scarred” senescence. We had already shown in the past (Baar .. de Keizer, Cell, 2017) that inhibition of FOXO4, or interference with its interaction with p53 using cell penetrating peptides could selectively eliminate senescent cells and target signs of aging in vivo. Today, I will show how we can use FOXO4-TP53 inhibitors against at least some therapy-surviving cancer cells. Last, I will show how we invested in optimization of these compounds to develop them towards clinical translation and how we can now very effectively eliminate certain types of therapy-surviving cancer cells. Altogether, this adds to a model where a senescent TME, as well as senescence-like cancer cells, can also promote cancer progression, migration, and therapy resistance by locally enforcing a state we called (cancer) “stem-lock”. And specific TP53-FOXO4 inhibitors may overcome this problem, thereby adding to a yin-yang treatment of damaging chemo-radiotherapy, followed by FOXO4-TP53-based anti-senescence treatment. Citation Format: Diana A. Putavet, Johannes Lehmann, Beatriz Subtil, Damon Hofman, Marjolein P. Baar, Peter L.J. de Keizer. Targeting senescence heterogeneity against cancer therapy-resistance and metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA002.

Redox metabolism: a double edge sword sustaining the adaptive resistance to therapy in cancer Metabolic reprogramming is a pivotal hallmark of cancer that contributes to therapy resistance (1). Cancer cells possess the remarkable ability to modify their metabolism, enabling them to regulate Reactive Oxygen Species (ROS) levels. Maintaining ROS at moderate levels facilitates cell survival and proliferation. Understanding the intricacies of cancer redox metabolism is crucial for identifying specific targets that can improve therapy efficacy. This Research Topic features three original research articles, two review articles, and one perspective article, which showcase recent advancements in this field. Collectively, these articles provide compelling evidence supporting the modulation of redox metabolism as a potent strategy to counteract adaptive resistance in cancer therapy. In their review article, Min et al. delve into the intricate role of cysteine, both bound to and free from proteins, in cancer biology. Cysteine, an amino acid, participates in several metabolic pathways, including the synthesis of reduced glutathione (GSH), a major endogenous non-enzymatic antioxidant. Additionally, cysteine plays a crucial role in generating sulfur-containing biomolecules, such as hydrogen sulfide (H 2 S), taurine, coenzyme A, and biotin (2). Furthermore, the oxidation of cysteine residues in numerous phosphatases, kinases, and transcription factors can modulate their activities, impacting cancer cell survival and therapy resistance. Given the pro-oxidant nature of most chemotherapeutic drugs, there is a growing interest in developing covalent inhibitors that specifically target cysteine residues near the ATP-binding pocket of redox signaling proteins. Moreover, GSH has been widely acknowledged for its crucial role in cancer progression and therapy resistance (3-5). Pompella et al.'s perspective article highlights the interaction of glycyl-cysteine, a dipeptide originating from GSH metabolism, with cisplatin. This interaction impedes cisplatin's access to cancer cells, reducing its cytotoxic efficacy. GGT1 expression emerges as a significant biomarker for cisplatin resistance. Notably, cisplatin-induced effects Frontiers in Oncology frontiersin.org 01

Cancer development and therapy resistance: spotlights on the dark side of the genome.

In this review, we summarized published articles on the role of tripartite motif (TRIM) family members in the initiation and development of human malignancies. The ubiquitin-proteasome system (UP-S) plays a critical role in cellular activities, and UP-S dysregulation contributes to tumorigenesis. One of the key regulators of the UP-S is the tripartite motif TRIM protein family, most of which are active E3 ubiquitin ligases. TRIM proteins are critical for the biological functions of cancer cells, including migration, invasion, metastasis, and therapy resistance. Therefore, it is important to understand how TRIM proteins function at the molecular level in cancer cells. We provide a comprehensive and up-to-date overview about the role TRIMs play in cancer progression and therapy resistance. We propose TRIM family members as potential new markers and targets to overcome therapy failure.

Proline, Glutamic-acid and Leucine-rich Protein 1 (PELP1) is a proto-oncogene that modulates ER signaling by functioning as an ER-coregulator. Emerging studies demonstrated that in a subset of breast tumors, PELP1 is predominantly localized in the cytoplasm and that PELP1 participates in extranuclear signaling by facilitating ER interactions with Src, PI3K, and AKT. PELP1 expression is upregulated in breast cancer, its deregulation contributes to therapy resistance, and PELP1 is a prognostic marker of poor survival. However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unknown. We have recently discovered that PELP1 has the potential to interact with mammalian target of rapamycin (mTOR), a serine/threonine kinase that forms two distinct complexes called mTORC1 (containing Raptor and PRAS40) and mTORC2 (containing Rictor and Protor). The objective of this application is to test whether crosstalk occurs between mTOR and PELP1 signaling axis and to test whether mTOR targeting drugs can be used to target PELP1 oncogenic functions. We have used breast cancer cells with PELP1 overexpression (MCF7-PELP1, ZR75-PELP1, T47D-PELP1) or PELP1 down regulation (MCF7-PELP1shRNA, ZR75-PELP1shRNA) along with controls to study the role of PELP1 in the regulation of mTOR axis. PELP1 knockdown significantly reduced downstream mTOR signaling components as analyzed by Western analysis using phospho-S6K, -4EBP1, -mTOR and -Akt, antibodies. Overexpression of PELP1 activated mTOR signaling components. Using immunoprecipitation, we have demonstrated that PELP1 interacts with mTOR. Further immunopreciptation analysis using Rictor and Raptor specific antibodies revealed that PELP1 associates with both TORC1 and TORC2 complexes. Using PELP1WT and PELP1cyto (that predominantly localizes in the cytoplasm), we have demonstrated the differential activation of mTOR signaling components: PELP1WT activated both TORC1 and TORC2 pathways, while PELP1cyto uniquely activated TORC2. mTOR targeting drugs (Rapamycin or AZD8055) showed a significant effect on the in vitro proliferation of PELP1 model cells. AZD8055 is more potent in reducing PELP1 driven tumor growth in vivo compared to rapamycin. Immunohistochemical studies on xenografts derived from MCF7, MCF7-PELP1WT and MCF7-PELP1cyto models demonstrated that PELP1 signaling modulates mTOR signaling in vivo and inhibition of mTOR signaling rendered PELP1 driven tumors to be highly sensitive to therapeutic inhibition. Further, mTOR inhibitors sensitized tamoxifen therapy resistant PELP1cyto model cells to hormonal therapy. IHC analysis of mammary glands and mammary tumors from PELP1Tg mice revealed deregulation of mTOR signaling components with excessive activation of S6K and 4EBP1. Using breast tumor tissue arrays (n = 100), we found significant correlation of PELP1 cytosolic localization with mTOR signaling. Collectively, the experimental results from these studies identified PELP1-mTOR axis as a novel component of PELP1 oncogenic functions and suggests, mTOR inhibitor(s) will be effective chemotherapeutic agents for down regulating PELP1 oncogenic functions and for blocking PELP1-mediated therapy resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-07.

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment, playing significant roles in cancer progression, immune evasion, and therapy resistance. Originating from circulating monocytes, TAMs can polarize into M1 and M2 phenotypes, with M2-like TAMs predominating in many cancers. This M2 polarization fosters an immunosuppressive environment that promotes tumor growth, metastasis, and resistance to therapies, including chemotherapy and immune checkpoint inhibitors. TAMs secrete various cytokines, chemokines, and growth factors that enhance tumor cell survival, promote angiogenesis, and recruit additional immunosuppressive cells such as regulatory T cells. They also express immune checkpoint molecules, further inhibiting effective anti-tumor immune responses. Given their dual role in supporting tumor survival and mediating immune evasion, TAMs represent an attractive target for therapeutic intervention. Current strategies to target TAMs include depletion, reprogramming, and combination therapies aimed at enhancing anti-tumor immunity. This review explores the complex biology of TAMs, their mechanisms of action in promoting cancer immunoevasion and therapy resistance, and the therapeutic strategies being developed to exploit their unique characteristics. By providing insights into the multifaceted roles of TAMs, this review aims to highlight potential avenues for improving cancer treatment outcomes and addressing the challenges posed by tumor-induced immune suppression. Keywords: Tumor-Associated Macrophages (TAMs), Immune Evasion, Therapy Resistance, Macrophage Polarization, Immunotherapy

The extracellular matrix (ECM) is a complex noncellular network of (macro-)molecules that surrounds and supports diverse cells in tissues and organs. In cancer, ECM is a part of the tumor microenvironment (TME) that embeds its cellular components including cancer cells and the neighboring non-cancerous stromal cells such as fibroblasts, endothelial, and immune cells. Given the complexity of players and interactions that the ECM participates in and is exposed to in the TME, it does not come as a surprise that many of the processes that drive cancer progression take part precisely in the ECM compartment of the TME. Along with diverse glycoproteins and collagens, proteoglycans (PGs) are among the main components of the core ECM. PGs are composed of a protein core to which glycosaminoglycan chains are attached. Considering the structural diversity of these molecules and their ‘hybrid’ nature, it is not surprising that they are involved in a variety of processes that are vital for surrounding cells. Moreover, they are secreted by both cancer and stromal cells, contributing to the complexity of interactions in the TME. In prostate cancer, PGs have been shown to be involved in many steps of its progression; the most prominent examples include the seemingly tumor-promoting roles of versican, perlecan, and biglycan, and the tumor-suppressive roles of decorin and betaglycan. The role of syndecan 1 is a bit more complex; namely, the nature of its role is context dependent. In this narrative review article, the roles of PGs in prostate cancer progression and therapy resistance are discussed in more detail.

Simple SummaryThe interactions between cancer cells and the surrounding blood vessels and peripheral nerves are critical in all the phases of tumor development. Accordingly, therapies that specifically target vessels and nerves represent promising anticancer approaches. The first aim of this review is to document the importance of blood vessels and peripheral nerves in both cancer onset and local or distant growth of tumoral cells. We then focus on the state-of-the-art therapies that limit cancer progression through the impairment of blood vessels and peripheral nerves. The mentioned literature is helpful for the scientific community to appreciate the recent advances in these two fundamental components of tumors.Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.

Tumor microenvironment is a complex network of epithelial cancer cells and non-transformed stromal cells. Of the many stromal cell types, fibroblasts are the most numerous ones and are traditionally viewed as supportive elements of cancer progression. Many studies show that cancer cells engage in active crosstalk with associated fibroblasts in order to obtain key resources, such as growth factors and nutrients. The facets of fibroblast "complicity to murder" in cancer are multiple. However, recent therapeutic attempts aiming at depleting fibroblasts from tumors, perturbed rather simplistic picture. Contrary to the expectations, tumors devoid of fibroblasts accelerated their progression while patients faced poorer outcomes. These studies remind us of the physiologic roles fibroblasts have in maintaining tissue homeostasis even in the presence of cancer. It is becoming increasingly clear that our research focus on advanced tumors has biased our understanding of fibroblast role in tumor biology. The numerous events where the fibroblasts protect the tissue from malignant transformation remain largely unacknowledged, as the tumors are invisible. The present review has the ambition to offer a more balanced view of fibroblasts functions in cancer progression and therapy resistance. We will address the question whether it is possible to synergize the efforts with fibroblasts as the therapeutic concept against tumor progression and therapy resistance.

Although resistance is its major obstacle in cancer therapy, trastuzumab is the most successful agent in treating epidermal growth factor receptor 2 positive (HER2 +) breast cancer (BC). Some patients show resistance to trastuzumab, and scientists want to circumvent this problem. This review elaborately discusses possible resistance mechanisms to trastuzumab and introduces mucin 1 (MUC1) as a potential target efficient for overcoming such resistance. MUC1 belongs to the mucin family, playing the oncogenic/mitogenic roles in cancer cells and interacting with several other oncogenic receptors and pathways, such as HER2, β-catenin, NF-κB, and estrogen receptor (ERα). Besides, it has been established that MUC1- Cytoplasmic Domain (MUC1-CD) accelerates the development of resistance to trastuzumab and that silencing MUC1-C proto-oncogene is associated with increased sensitivity of HER2+ cells to trastuzumab-induced growth inhibitors. We mention why targeting MUC1 can be useful in overcoming trastuzumab resistance in cancer therapy.

Emerging insights into lineage plasticity in pancreatic cancer initiation, progression, and therapy resistance.

Homeostatic Restoration of Desmoplastic Stroma Rather Than Its Ablation Slows Pancreatic Cancer Progression

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, and therapy resistance is one of the most common reasons for treatment failure in CRC. Cancer stem cells (CSCs) are a minor subpopulation of tumor cells with the capacity of self-renewal and differentiation, which play an important role in the progression, recurrence, and therapy resistance of cancer. Recent studies have shown that CSCs induce cancer resistance to conventional treatments through a variety of mechanisms, including targeting signaling pathways, regulating level of microRNAs, DNA damage repair, maintaining low levels of reactive oxygen species (ROS), and maintaining a relatively quiescent state. Therefore, therapeutic strategies targeting CSCs may be able to reverse therapy resistance of CRC, but the lack of specific CSC markers also confuses this therapeutic strategy. In this chapter, we will discuss the effect of CSCs on CRC therapy resistance and its potential mechanism, the current research progress of the strategy of targeting CSCs, and their existing problems in order to provide a reference for the selection of therapeutic strategies for CRC.KeywordsColorectal cancerCancer stem cellsTherapy resistanceSignaling pathwaysMicroRNADNA damageReactive oxygen species

Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer - the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives - was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, weprovide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. Wediscuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.