Dormant Cancer Research Articles

A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells.

Cancer microenvironments encompass both cancer-promoting and cancer-restraining factors. If these factors cancel each other, cancer dormancy may ensue. In search of microenvironmental factors that keep dormant lung-metastasizing neuroblastoma cells and brain-metastasizing melanoma cells (BMMC) in check, we identified the beta subunit of hemoglobin and a heterodimer of alpha and beta chains of hemoglobin (α/β dimer) in the lung and brain microenvironments, respectively, as anti-metastatic factors. A previous study demonstrated that the α/β dimer triggers programmed cell death of BMMC and downregulates the expression of BRD4, GAB2, and IRS2 proteins, which perform essential functions in tumorigenesis and progression. The working hypothesis of the present study is that in addition to its tumoricidal function, the α/β dimer serves as a pathfinder for the identification of therapy targets for BMMC. We, therefore, employed small-molecule inhibitors of Bromodomain-containing protein 4 (BRD4), GRB2-associated-binding protein 2 (GAB2), and Insulin receptor substrate 2 (IRS2) as potential anti-BMMC agents. A combination of sub-lethal concentrations of BRD4 and IRS2 inhibitors synergistically arrested BMMC at the subG1 phase of the cell cycle and killed more than 70% of BMMCs. The BRD4/IRS2 inhibitor cocktail (designated hereafter as BRIRi) moderated the malignancy of BMMC lines from four different human melanomas. Preliminary results suggest that the BRIRi modulated "cold" BMMC to "hot" ones. Among the top enriched functions of differentially expressed genes identified by RNAseq of BRIRi-treated versus control BMMC, TNF and apoptotic signaling pathways were observed. We propose that co-targeting BRD4 and IRS2 offers a promising approach for treating BMMC.

Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse.

Cellular plasticity mediates tissue development as well as cancer growth and progression. In breast cancer, a shift to a more epithelial phenotype (epithelialization) underlies a state of reversible cell growth arrest called tumor dormancy, which enables drug resistance, tumor recurrence, and metastasis. Here, we explored the mechanisms driving epithelialization and dormancy in aggressive mesenchymal-like breast cancer cells in three-dimensional cultures. Overexpressing either of the epithelial lineage-associated transcription factors OVOL1 or OVOL2 suppressed cell proliferation and migration and promoted transition to an epithelial morphology. The expression of OVOL1 (and of OVOL2 to a lesser extent) was regulated by steroid hormones and growth factors and was more abundant in tumors than in normal mammary cells. An uncharacterized and indirect target of OVOL1/2, C1ORF116, exhibited genetic and epigenetic aberrations in breast tumors, and its expression correlated with poor prognosis in patients. We further found that C1ORF116 was an autophagy receptor that directed the degradation of antioxidant proteins, including thioredoxin. Through C1ORF116 and unidentified mediators, OVOL1 expression dysregulated both redox homeostasis (in association with increased ROS, decreased glutathione, and redistribution of the transcription factor NRF2) and DNA damage and repair (in association with increased DNA oxidation and double-strand breaks and an altered interplay among the kinases p38-MAPK, ATM, and others). Because these effects, as they accumulate in cells, can promote metastasis and dormancy escape, the findings suggest that OVOLs not only promote dormancy entry and maintenance in breast cancer but also may ultimately drive dormancy exit and tumor recurrence.

Abstract 5100: Mediator subunit Med4 enforces metastatic dormancy in breast cancer

Long term survival of breast cancer patients is limited due to recurrence from metastatic dormant cancer cells. However, the mechanisms by which these dormant breast cancer cells survive and awaken remain poorly understood. Our unbiased genome-scale genetic screen in mice identified Med4 as a novel cancer-cell intrinsic gatekeeper in metastatic reactivation. MED4 haploinsufficiency is prevalent in metastatic breast cancer patients and correlates with poorer prognosis. Syngeneic xenograft models revealed that Med4 enforces breast cancer dormancy. Contrary to the canonical function of the Mediator complex in activating gene expression, Med4 maintains 3D chromatin compaction and enhancer landscape, by preventing enhancer priming or activation through the suppression of H3K4me1 deposition. Med4 haploinsufficiency disrupts enhancer poise and reprograms the enhancer dynamics to facilitate extracellular matrix (ECM) gene expression and integrin-mediated mechano-transduction, driving metastatic growth. Our findings establish Med4 as a key regulator of cellular dormancy and a potential biomarker for high-risk metastatic relapse. Citation Format: Seong-Yeon Bae, Hsiang-Hsi Ling, Yi Chen, Hong Chen, Dhiraj Kumar, Jiankang Zhang, Aaron Viny, Ronald A. DePinho, Filippo G. Giancotti. Mediator subunit Med4 enforces metastatic dormancy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5100.

Abstract 4048: The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion

Abstract The mechanisms that regulate cancer dormancy remain poorly understood. Using an orthotopic mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified the transcriptional repressor factor Dec2 (Bhlhe41) as a gene that was upregulated in metastatic dormant tumor cells from the liver. To understand how Dec2 regulates dormancy, we deleted it from the murine pancreatic cancer cells and implanted them in the model. Following resection, mice implanted with Dec2 KO cells demonstrated a striking improvement in survival compared to the mice with Dec2 WT cells. This difference in survival was abrogated when nude mice were used as hosts indicating the survival difference is from an immune mediated mechanism. Pancreatic cancer is a highly immunosuppressive tumor due to both a relatively low expression of major histocompatibility complex class I (MHC-I)-dependent antigen presentation and an abundance of myeloid-derived suppressor cells that lead to poor T cell trafficking and activation. We found that deletion of Dec2 overcame both of these mechanisms to restore anti-tumor immunity that inhibited tumor growth not only in primary tumors as well as metastases. Dec2 suppresses MHC-I antigen presentation by repressing multiple genes in the antigen presentation pathway including H2-k1, H2-d1, Tap1, and B2m as well as the source of tumor antigens from the proteosome by repressing multiple proteasome genes. Loss of Dec2 repolarized the tumor immune microenvironment by decreasing expression of multiple immunosuppressive cytokines such as Cxcl1, Ccl2 and Csf2 in tumors. We conclude that Dec2 facilitates both pancreatic tumor growth and dormancy by regulating tumor cell MHCI antigen presentation. Dec2 is known to function as part of a negative accessory arm of the molecular circadian clock. We found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock. Citation Format: Lan Wang, Chris Harris, Orjola Prela, Wade Narrow, Jennifer L. Becker, Juliana Cazarin de Menezes, Darren R. Carpizo. The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4048.

Abstract 164: Heterogeneous dormant breast cancer cells leverage bone marrow cell plasticity at the single-cell level to drive metastasis initiation

Abstract 164: Heterogeneous dormant breast cancer cells leverage bone marrow cell plasticity at the single-cell level to drive metastasis initiation

Abstract 3826: Awakened dormant cancer cells undergo highly mesenchymal to quasi-mesenchymal transition and acquire stemness

Abstract 3826: Awakened dormant cancer cells undergo highly mesenchymal to quasi-mesenchymal transition and acquire stemness

Abstract 5101: Collagen I helps maintain cancer dormancy under metabolic stress

Abstract Cancer progression is driven by a combination of intrinsic and extrinsic stresses and reciprocal interactions between cancer cells and the extracellular matrix (ECM). Type I collagen is the most abundant ECM component in the human body. One hallmark of cancer progression is the elevated deposition and cross-linking of collagen, which regulates various cellular processes, including migration, proliferation, and apoptosis. Here, we report that under metabolically stressed conditions, cancer cells directly consume collagen to survive. Nutrient deprivation suppressed cell proliferation, evidenced by decreased levels of PNCA and Ki67 as measured by RT-PCR and confirmed by EdU immunofluorescence assay. Intriguingly, there was a significant increase in cancer stem cell (CSC)-associated markers -CD133, Sox2, Nanog, Oct4, ALDH1-at both mRNA and protein levels, compared to normal culture control. This trend persisted in cells cultured in both serum-free and exhausted (low pH and nutrient-derived) media, suggesting that metabolic stress from nutrient deprivation promotes cancer cells into a dormant and de-differentiated state. Notably, cells cultured on collagen gels showed superior survival under all conditions. In addition, cellular quiescence was confirmed via increased expression of p27 and a higher percentage of cells entered G0-G1 cell cycle arrest in the absence of collagen (∼90%) compared to those on collagen gels (∼70%). This pattern was consistent with the lower CSC expression observed in collagen gels, suggesting that collagen not only supports cell survival but may also act as a nutrient reservoir to mitigate metabolic stress. By employing a perfusion-enabled 3D patient-derived ex vivo model developed in our laboratory, we demonstrated significantly higher metabolic activity in the microtumors cultured in collagen-conjugated scaffold and active media transport, compared to static conditions. This was evidenced by increases in total cell number, percent viability, and EdU-positive cells. We also conducted long-term continuous confocal time-lapse imagings revealing that cancer cells actively uptake FITC-conjugated collagen for survival, enabling them to remain quiescent for up to 36 days. We were able to track and monitor cell activities at the same regions of interest over time to demonstrate cellular dormancy. This study provides compelling evidence that metabolic stress triggers a dormant phenotype in cancer cells, with enhanced stemness potential for cancer re-initiation and relapse. Our findings suggest that type I collagen acts as a vital nutrient reservoir for cancer cells under metabolic stress, aiding in the maintenance of their dormant state. Citation Format: Laxmi Swetha Karanam, Zoe Zhou, Said J. Cifuentes Maury, Marilena Tauro, Conor C. Lynch, Duy T. Nguyen. Collagen I helps maintain cancer dormancy under metabolic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5101.

Dormancy in Metastatic Colorectal Cancer: Tissue Engineering Opportunities for In Vitro Modeling.

Colorectal cancer (CRC) recurs at a striking rate, specifically in patients with liver metastasis. Dormant CRC cells disseminated following initial primary tumor resection or treatment often resurface years later to form aggressive, therapy-resistant tumors that result in high patient mortality. Routine imaging-based screenings often fail to detect dormant cancer cell clusters, and there are no overt symptomatic presentations, making dormant CRC a major clinical challenge to diagnose and treat. Tissue engineering approaches are ideally suited to model dormant cancer cells and enable the discovery of therapeutic vulnerabilities or unique mechanistic dependencies of dormant CRC. Emerging evidence suggests that tissue-engineered approaches have been successfully used to model dormant breast and lung cancer. With CRC responsible for the second most cancer-related deaths worldwide and CRC patients commonly experiencing recurrence, it is essential to expand dormancy models to understand this phenomenon in the context of CRC. Most published in vitro models of CRC dormancy simplify the complex tumor microenvironment with two-dimensional culture systems to elucidate dormancy-driving mechanisms. Building on this foundation, future research should apply tissue engineering methods to this growing field to generate competent three-dimensional models and increase mechanistic knowledge. This review summarizes the current state of in vitro CRC dormancy models, highlighting the techniques utilized to give rise to dormant CRC cells: nutrient depletion, anticancer drugs, physical extracellular matrix interactions, and genetic manipulation. The metrics used to validate dormancy within each model are also consolidated to demonstrate the lack of established standards and the ambiguity around comparing studies that have been validated differently. The methods of these studies are organized in this review to increase comprehensibility and identify needs and opportunities for future bioengineered in vitro models to address dormancy-driven mortality in patients with CRC liver metastasis. Impact Statement Dormant cancer drives high patient mortality, especially in metastatic colorectal cancer, owing to the clinical inability to identify dormant cells prior to their overt recurrence. Lacking clinical insights, in vitro modeling for mechanistic and therapeutic discovery is hindered. Here, we review models and methods of inducing colorectal cancer dormancy with the goal of consolidating findings for reference. We also highlight the need for advanced, tissue-engineered models to better mimic the organ-specific 3D microenvironment of metastatic colorectal cancer. New models would enable breakthroughs in understanding mechanisms driving dormancy progression and reversal, thereby providing context for therapeutic advances to improve patient survival.

De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.

De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.

Advances in Targeting Neutrophil Extracellular Traps as a Promising Approach for Breast Cancer Treatment.

Neutrophils release neutrophil extracellular traps (NETs), a reticular structure mainly composed of antimicrobial peptides, DNA, and histones. Neutrophil elastase (NE), matrix metalloproteinase- 9, and histone G are the key components of NETs critically involved in breast cancer invasion and migration, which suggests an important role of NETs in tumorigenesis and metastasis. Studies have reported that NETs significantly promote breast cancer invasion, intravascular infiltration, and distant metastasis by inducing epithelial-mesenchymal transition (EMT), remodeling the extracellular matrix, and modulating the immune microenvironment. Meanwhile, NETs also function crucially in capturing circulating tumor cells, forming a pre-metastatic microenvironment, and awakening dormant cancer cells. Notably, NETs are also closely associated with chemotherapy and immunotherapy resistance in breast cancer. Therapeutic strategies targeting NETs, including DNase I, PAD4 inhibitors, elastase inhibitors, and histone C inhibitors, have been widely studied. These targeted therapies can effectively suppress the generation of NETs, improve drug efficacy, and delay tumor metastasis. This review aimed to systematically elucidate the mechanism of action of NETs in the progression and drug resistance of breast cancer and explore potential targeted therapeutic strategies against NETs. These strategies could effectively inhibit the generation of NETs, delay the progression of breast cancer, and improve therapeutic efficacy. An in-depth study of the mechanism of action of NETs and the clinical significance of their targeted interventions is expected to provide a new direction for breast cancer treatment.

Breast Cancer Dormancy – Lessons Learnt

Despite early diagnosis and improved treatments, breast cancer remains a challenging disease. A strategic advantage for breast cancer recurrence is the ability of breast cancer cells to become quiescent and survive for decades in a dormant state within the endosteal region of the bone marrow. Breast cancer dormancy is triggered by exosome vesicles secreted by mesenchymal stem cells residing in the bone marrow. By mechanisms yet to be determined, dormant breast cancer cells are awakened leading to resurgence and metastasis. Experimental evidence supports the notion that dormant breast cancer cells are cancer stem cells recognized as tumor initiating and propagating cells with chemoresistant and metastatic properties. These cells represent less than 2% of the total tumor mass, which impose a significant barrier for their therapeutic targeting. This review focuses on cellular and molecular properties of breast cancer dormancy including tumor microenvironment, epigenetic regulation, cell signaling and metabolic reprogramming.

Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer.

Head and neck cancers harbor dormant cancer stem cells (CSCs). This study explores how platinum therapy impacts these cells in a non-genetic manner and the role of hypoxia in this process. Previously, we identified a novel population of CSCs exhibiting an "altruistic" phenotype, sacrificing self-renewal to promote niche defense (tumor stemness defense, TSD), potentially protecting a dormant subpopulation of CSCs, the reawakening CSC (R-CSC) retaining stress memory. This TSD phenotype involves the activation of the MYC-HIF2α pathway and, importantly, is linked to a hypoxic tumor microenvironment. We termed these TSD+ CSCs "altruistic cancer stem cells" (A-CSCs). Here we investigated the potential role of tumor hypoxia in the mobilization of TSD+ CSCs to the circulation as a part of niche defense against platinum therapy. We isolated CTCs and primary tumor cells from head and necksquamous cell carcinoma (HNSCC) patients undergoing platinum therapy (n = 14). We analyzed the TSD phenotype and markers of hypoxia in these cells. Additionally, we further characterized a previously reported pre-clinical model of platinum-induced tumor stemness to study the link between hypoxia, TSD+ CSC emergence, and mobilization to the circulation and bone marrow. We isolated TSD+ CTCs with a hypoxic signature from eight out of 14 HNSCC patients. These cells displayed increased proliferation and invasion upon cisplatin treatment, suggesting a role in niche defense. Our pre-clinical model confirmed that hypoxia directly correlates with the expansion of TSD+ CSCs and their mobilization into the circulation and bone marrow following cisplatin treatment. We demonstrated the protection of R-CSCs by TSD+ CSCs. Notably, inhibiting hypoxia alone with tirapazamine did not reduce TSD+ CSCs, CTCs, or R-CSCs. However, combining tirapazamine with FM19G11, a MYC-HIF2α pathway inhibitor, significantly reduced the platinum-induced expansion of both TSD+ CSCs, CTCs, and the presence of R-CSCs in the bone marrow. This study reveals that HNSCC patients undergoing platinum therapy can harbor TSD+ CTCs exhibiting an altruistic phenotype and a hypoxic signature. Additionally, the pre-clinical study provides a novel non-genetic mechanism of therapy resistance-the altruistic tumor self-defense. The tumor microenvironment, through the emergence of TSD+ CSCs, appears to act collectively to defend the tumor self-identity by hijacking an altruistic stem cell niche defense mechanism.

Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis.

Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis.

Exploiting Cancer Dormancy Signaling Mechanisms in Epithelial Ovarian Cancer Through Spheroid and Organoid Analysis.

Epithelial ovarian cancer (EOC) exhibits a unique mode of metastasis, involving spheroid formation in the peritoneum. Our research on EOC spheroid cell biology has provided valuable insights into the signaling plasticity associated with metastasis. We speculate that EOC cells modify their biology between tumour and spheroid states during cancer dormancy, although the specific mechanisms underlying this transition remain unknown. Here, we present novel findings from direct comparisons between cultured EOC spheroids and organoids. Our results indicated that AMP-activated protein kinase (AMPK) activity was significantly upregulated and protein kinase B (Akt) was downregulated in EOC spheroids compared to organoids, suggesting a clear differential phenotype. Through RNA sequencing analysis, we further supported these phenotypic differences and highlighted the significance of cell cycle regulation in organoids. By inhibiting the G2/M checkpoint via kinase inhibitors, we confirmed that this pathway is essential for organoids. Interestingly, our results suggest that specifically targeting aurora kinase A (AURKA) may represent a promising therapeutic strategy since our cells were equally sensitive to Alisertib treatment as both spheroids and organoids. Our findings emphasize the importance of studying cellular adaptations of EOC cells, as there may be different therapeutic targets depending on the step of EOC disease progression.

Exploring B7-H4's Role in Prostate Cancer Dormancy after Androgen Deprivation Therapy: Extracellular Matrix Interactions and Therapeutic Opportunities.

Prostate cancer is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique prostate cancer patient-derived xenograft dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of patients with prostate cancer treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within the dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during prostate cancer dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.

The Roles of Myeloid Cells in Breast Cancer Progression.

This chapter reviews tumor-associated myeloid cells, including macrophages, neutrophils, and other innate immune cells, and their multifaceted roles in supporting breast cancer progression and metastasis. In primary tumors, myeloid cells play key roles in promoting tumor epithelial-mesenchymal transition (EMT) and invasion. They can facilitate intravasation (entry into the bloodstream) and colonization, disrupting the endothelial cell layer and reshaping the extracellular matrix. They can also stimulate angiogenesis, suppress immune cell responses, and enhance cancer cell adaptability. In the bloodstream, circulating myeloid cells enable the survival of disseminated tumor cells via immunosuppressive effects and physical shielding. At the metastatic sites, they prime the premetastatic niche, facilitate tumor cell extravasation, and support successful colonization and outgrowth. Mechanistically, myeloid cells enhance cancer cell survival, dormancy escape, proliferation, and mesenchymal-epithelial transition (MET). Nonetheless, substantial gaps in our understanding persist regarding the functional and spatiotemporal diversity, as well as the evolutionary patterns, of myeloid cells during metastatic progression. Myeloid cell plasticity and differential responses to therapies present key barriers to successful treatments. Identifying specific pro-tumoral myeloid cell subpopulations and disrupting their interactions with cancer cells represent promising therapeutic opportunities. Emerging evidence suggests combining immunomodulators or stromal normalizers with conventional therapies could help overcome therapy-induced immunosuppression and improve patient outcomes. Overall, further elucidating myeloid cell heterogeneity and function throughout the process of breast cancer progression and metastasis will enable more effective therapeutic targeting of these critical stromal cells.

Microenvironmental Regulation of Dormancy in Breast Cancer Metastasis: "An Ally that Changes Allegiances".

Breast cancer remission after treatment is sometimes long-lasting, but in about 30% of cases, there is a relapse after a so-called dormant state. Cellular cancer dormancy, the propensity of disseminated tumor cells (DTCs) to remain in a nonproliferative state for an extended period, presents an opportunity for therapeutic intervention that may prevent reawakening and the lethal consequences of metastatic outgrowth. Therefore, identification of dormant DTCs and detailed characterization of cancer cell-intrinsic and niche-specific [i.e., tumor microenvironment (TME) mediated] mechanisms influencing dormancy in different metastatic organs are of great importance in breast cancer. Several microenvironmental drivers of DTC dormancy in metastatic organs, such as the lung, bone, liver, and brain, have been identified using in vivo models and/or in vitro three-dimensional culture systems. TME induction and persistence of dormancy in these organs are mainly mediated by signals from immune cells, stromal cells, and extracellular matrix components of the TME. Alterations of the TME have been shown to reawaken dormant DTCs. Efforts to capitalize on these findings often face translational challenges due to limited availability of representative patient samples and difficulty in designing dormancy-targeting clinical trials. In this chapter, we discuss current approaches to identify dormant DTCs and provide insights into cell-extrinsic (i.e., TME) mechanisms driving breast cancer cell dormancy in distant organs.

GO-CRISPR: A highly controlled workflow to discover gene essentiality in loss-of-function screens.

Genome-wide CRISPR screens are an effective discovery tool for genes that underlie diverse cellular mechanisms that can be scored through cell fitness. Loss-of-function screens are particularly challenging compared to gain-of-function because of the limited dynamic range of decreased sgRNA sequence detection. Here we describe Guide-Only control CRISPR (GO-CRISPR), an improved loss-of-function screening workflow, and its companion software package, Toolset for the Ranked Analysis of GO-CRISPR Screens (TRACS). We demonstrate a typical GO-CRISPR workflow in a non-proliferative 3D spheroid model of dormant high grade serous ovarian cancer and demonstrate superior performance to standard screening methods. The unique integration of the pooled sgRNA library quality and guide-only controls allows TRACS to identify novel molecular pathways that were previously unidentified in tumor dormancy and undetectable to analysis packages that lack the guide only controls. Together, GO-CRISPR and TRACS can robustly improve the discovery of essential genes in challenging biological scenarios such as growth arrested cells.

Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors

Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (ENZ-R) cellular models to elucidate NR2F1 as a key factor in lineage transition and ENZ resistance. Depletion of NR2F1 drives ENZ-R cells into a relative dormancy state, characterized by reduced proliferation and heightened drug resistance, while NR2F1 overexpression yields contrasting outcomes. Transcriptional sequencing analysis of NR2F1-silenced prostate cancer cells and tissues from the Cancer Genome Atlas-prostate cancer and SU2C cohorts indicated exosomes as the most enriched cell component, with pathways implicated in steroid hormone biosynthesis and drug metabolism. Moreover, NR2F1-AS1 forms a complex with SRSF1 to upregulate NR2F1 expression, facilitating its binding with ESR1 to sustain hormonal receptor expression and enhance proliferation in ENZ-R cells. Furthermore, HnRNPA2B1 interacts with NR2F1 and NR2F1-AS1, assisting their packaging into exosomes, wherein exosomal NR2F1 and NR2F1-AS1 promote the proliferation of dormant ENZ-R cells. Our works offer novel insights into the reawaking of dormant drug-resistant cancer cells governed by NR2F1 upregulation triggered by exosome-derived NR2F1-AS1 and NR2F1, suggesting therapeutic potential for phenotype reversal.Graphical

Cancer Cells in Sleep Mode: Wake Them to Eliminate or Keep Them Asleep Forever?

Cancer cell dormancy is a critical phase in cancer development, wherein cancer cells exist in a latent state marked by temporary but reversible growth arrest. This dormancy phase contributes to anticancer drug resistance, cancer recurrence, and metastasis. Treatment strategies aimed at cancer dormancy can be categorized into two contradictory approaches: inducing cancer cells into a dormant state or eliminating dormant cells. While the former seeks to establish permanent dormancy, the latter aims at eradicating this small population of dormant cells. In this review, we explore the current advancements in therapeutic methods targeting cancer cell dormancy and discuss future strategies. The concept of cancer cell dormancy has emerged as a promising avenue for novel cancer treatments, holding the potential for breakthroughs in the future.