Tumor dormancy

UNLABELLED: Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. Using spatial transcriptomics in patient derived xenograft models, we capture clonal lineage evolution during treatment, finding the persister state to show increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients...

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 or 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, treatment, and opportunities for possibly curative interventions...

The immune escape stage in cancer immunoediting is a pivotal feature, transitioning immune-controlled tumor dormancy to progression, and augmenting invasion and metastasis. Tumors employ diverse mechanisms for immune escape, with generating immunosuppressive cells from skewed hematopoiesis being a crucial mechanism. This led us to suggest that tumor cells with immune escape properties produce factors that induce dysregulations in hematopoiesis. In support of this suggestion, this study found that mice bearing advanced-stage tumors exhibited dysregulated hematopoiesis characterized by the development of splenomegaly, anemia, extramedullary hematopoiesis, production of immunosuppressive mediators, and expanded medullary myelopoiesis...

In a recent study in Cancer Cell, Sreekumar et al. used therapy-associated breast cancer mouse models as well as in vitro dormancy models to identify extracellular matrix (ECM)-related tumor cell-autonomous mechanisms of dormancy in residual tumor cells (RTCs). The study reveals an important role of the glycosylation of proteoglycans in sustaining dormancy and opens the door to leverage this biology to eliminate RTCs and prevent recurrence.

Dormancy is a potential way for tumors to develop drug resistance and escape treatment. However, the mechanisms involved in cancer dormancy remain poorly understood. This is mainly because there is no in vitro culture model making it possible to spontaneously induce dormancy. In this context, the present work proposes the use of three-dimensional (3D) spheroids developed from osteosarcoma cell lines as a relevant model for studying cancer dormancy. MNNG-HOS, SaOS-2, 143B, MG-63, U2OS and SJSA-1 cell lines were cultured in 3D using the Liquid Overlay Technique (LOT)...

BACKGROUND: Dormant cancer cells are commonly known to play a pivotal role in cancer recurrence and metastasis. However, the mechanism of tumor dormancy and recurrence remains largely unknown. This study aimed to investigate the mechanism by which exosomes derived from dormant lung adenocarcinoma (LUAD) cells activate cancer-associated fibroblasts (CAFs) to reconstruct the extracellular matrix (ECM), providing a novel idea for decoding the mechanism of tumor dormancy. METHODS: In this study, high-dose cisplatin was used to induce the dormant LUAD cells...

The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis...

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...

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...

PURPOSE OF REVIEW: Cellular dormancy is a major contributor to cancer progression and recurrence. This review explores recent findings on the molecular mechanisms implicated in cancer dormancy and investigates potential strategies to improve therapeutic interventions. RECENT FINDINGS: Research on cancer dormancy reveals a complex and multifaceted phenomenon. Providing a latent reservoir of tumor cells with reduced proliferation and enhanced drug-tolerance, dormant cancer cells emerge from a clonally diverse population after therapy or at metastatic sites...

Disseminated tumor cells frequently exhibit a period of dormancy, rendering them chemotherapy insensitive; conversely, the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy administration enhances metastatic colonization and outgrowth. In vitro , chemotherapy-treated fibroblasts display a pro-tumorigenic senescence-associated secretory phenotype (SASP) and are effectively eliminated by targeting the anti-apoptotic protein BCL-xL...

Survival of dormant, disseminated breast cancer (BC) cells contributes to tumor relapse and metastasis. Women with a body mass index greater than 35 have an increased risk of developing metastatic recurrence. Herein, we investigated the effect of diet-induced obesity (DIO) on primary tumor growth and metastatic progression using both metastatic and systemically dormant mouse models of BC. This approach led to increased PT growth and pulmonary metastasis. We developed a novel protocol to induce obesity in Balb/c mice by combining dietary and hormonal interventions with a thermoneutral housing strategy...

BACKGROUND: Hypoxia has been shown to induce cancer cells to become dormant meanwhile these cells inclined to disseminate and eventually cause metastasis. However, the molecular mechanism is still elusive. The purpose is to explore whether dormancy-associated microRNAs (DmiRs) get involved in hypoxia-induced cell dormancy of salivary adenoid cystic carcinoma (SACC). MATERIAL AND METHODS: This study performed multi-perspective investigation of the biological effects of miR-922/DEC2 on SACC based on clinical samples, 2D and 3D in vitro model and nude mice in vivo model, based on our previous study of overexpression of DEC2 inducing SACC cellular dormancy...

Immunotherapy has dramatically transformed the cancer treatment landscape largely due to the efficacy of immune checkpoint inhibitors (ICIs). Although ICIs have shown promising results for many patients, the low response rates in many cancers highlight the ongoing challenges in cancer treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms: a fast-acting, perforin-mediated process and a slower, Fas ligand (FasL)-driven pathway. Evidence also suggests that the preferred killing mechanism of CTLs depends on the antigenicity of tumor cells...

The histone deacetylase sirtuin 6 (SIRT6) has been endowed with anti-cancer capabilities in many tumor types. Here, we investigate the impact of SIRT6-overexpression (SIRT6-OE) in Delta16HER2 mice, which are a bona fide model of HER2-positive breast cancer. After an initial delay in the tumor onset, SIRT6-OE induces a more aggressive phenotype of Delta16HER2 tumors promoting the formation of higher number of tumor foci and metastases than controls. This phenotype of SIRT6-OE tumors is associated with cancer stem cell (CSC)-like features and tumor dormancy, and low senescence and oxidative DNA damage...

Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness...

Cellular or tumor dormancy, identified recently as one of the main reasons behind post-therapy recurrence, can be caused by diverse reasons. Chemotherapy has recently been recognized as one of such reasons. However, in-depth studies of chemotherapy-induced dormancy are lacking due to the absence of an in vitro human-relevant model tailor-made for such a scenario. This report utilized multicellular breast cancer spheroid to create a primary platform for establishing a chemotherapy-induced dormancy model. It is observed that extreme chemotherapeutic stress affects invasive and non-invasive spheroids differently...

Cell adhesion to the extracellular matrix (ECM) is required for normal cell cycle progression and accurate cell division. However, how cell adhesion to the wide range of ECM proteins found in human tissues influences the cell cycle is not fully understood. The composition and physical properties of the ECM can have profound effects on cell proliferation but can also promote cell cycle exit and quiescence. Furthermore, during tumor development and progression, changes in the ECM can drive both cancer cell proliferation and dormancy...

Breast cancer metastatic relapse after a latency period, known as metastatic dormancy. Through genetic screening in mice, we identified the mediator complex subunit 4 ( Med4 ) as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation. Med4 downregulation effectively awakened dormant breast cancer cells, prompting macroscopic metastatic outgrowth in the lungs. Med4 depletion results in profound changes in nuclear size and three-dimensional chromatin architecture from compacted to relaxed states in contrast to the canonical function of the Mediator complex...

OBJECTIVE: The purpose of this paper is to promote the medical treatment of colorectal cancer in our country and to save the lives of patients with colorectal cancer by studying mammalian target of rapamycin (mTOR) and the biologic information analysis of colorectal cancer. METHODS: We analyzed mTOR expression and survival differences using data from Coad & read from the TCGA public database and explored the coexpression regulatory network of mTOR. mTOR-regulated mirnas were screened using the Linked Omics database...