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Intravital two-photon microscopy of cancer cells colonizing bone. (a) Still-frames capturing the arrival of a circulating tumour cell (top panels) and colonizing tumour cell (bottom panels) in real time. Blue, bone; red, vasculature; green, 5TGM1-GFP myeloma cells. Scale bars, 50 μm. It corresponds to Supplementary Movies 1 and 2. (b) Still-frames of the same cells in a showing egress of circulating cell from bone after 2 min and retention of a colonizing cell >1 h in the bone. Blue, bone; red, vasculature; green, 5TGM1-GFP myeloma cells. Scale bars, 20 μm. (c) Proportion of cells that circulated through or colonized the bone marrow in each experiment and total of all experiments. (d) CD138-stained sections from naive, or cell-injected mice at 1 and 3 days post injection. Single CD138+ cells (brown, black arrows), haematoxylin counterstain. Scale bars, 20 μm. Data represent at least three experiments.
Source publication
Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control o...
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recognised to become dormant through a Notch2-dependent mechanism. We found that Notch2High human BrCa MDA-MB231 (MDA) cells also expressed high level of N-Cadherin. This prompted us to hypothesize that N-Cadherin could have a role in MDA-SNO interaction. Of no...
Citations
... PDAC-derived lung metastatic cell lines were labelled with CellTracker Membrane Dye CM-DiI (Invitrogen) as described previously 61 . CM-Dil + and CM-DiI − populations were isolated using FACS at the indicated timepoints. ...
Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial–mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.
... In contrast, colonization of a perivascular ecological niche enriched with hematopoietic stem cells promoted active proliferation and facilitated the formation of metastatic lesions. In a study conducted by Lawson MA [18] et al., the behavior of individual myeloma cells was meticulously tracked through live imaging, leading to the validation of their colonization within the endosteal niche. Furthermore, it was observed that these myeloma cells entered a state of dormancy upon colonization, followed by subsequent activation that facilitated the formation of cellular colonies. ...
... The regulation of tumor cell dormancy reversibility encompasses intracellular and external environmental factors. Lawson et al. [18] demonstrated the dynamic nature of dormancy, showing its induction via interactions with bone lining cells or osteoblasts, and cessation through osteoclast-mediated endosomal ecotone remodeling. Importantly, this process is reversible, indicating dormant cells' capability to transition between dormant and active states in response to the bone microenvironment's dynamic interplay. ...
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.
... More importantly, NCX1 induced calcium influx of MM cells promoted RANKLinduced osteoclast differentiation [21]. Studies have confirmed that the BM microenvironment, especially BM osteoclasts, play a central role in supporting MM cell survival and drug resistance [22,23]. It is unclear whether NCX1 can affect the BTZ sensitivity of MM through osteoclasts . ...
Although bortezomib (BTZ) is the cornerstone of anti-multiple myeloma (MM) therapy, the inevitable primary and secondary drug resistance still seriously affects the prognosis of patients. New treatment strategies are in need. Sodium-calcium exchanger 1 (NCX1) is a calcium-permeable ion transporter on the membrane, and our previous studies showed that low NCX1 confers inferior viability in MM cells and suppressed osteoclast differentiation. However, the effect of NCX1 on BTZ sensitivity of MM and its possible mechanism remain unclear. In this study, we investigated the effect of NCX1 on BTZ sensitivity in MM, focusing on cellular processes of autophagy and cell viability. Our results provide evidence that NCX1 expression correlates with MM disease progression and low NCX1 expression increases BTZ sensitivity. NCX1/Ca²⁺ triggered autophagic flux through non-canonical NFκB pathway in MM cells, leading to attenuated the sensitivity of BTZ. Knockdown or inhibition of NCX1 could potentiate the anti-MM activity of BTZ in vitro and vivo, and inhibition of autophagy sensitized NCX1-overexpressing MM cells to BTZ. In general, this work implicates NCX1 as a potential therapeutic target in MM with BTZ resistance and provides novel mechanistic insights into its vital role in combating BTZ resistance.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-024-01628-4.
... Therefore, the ability for breast cancer cells to home to the bone is not sufficient as an explanation for the formation of osteolytic lesions. There is similar evidence for both prostate cancer (23)(24)(25)(26) and multiple myeloma-induced bone disease (7,27,28) pointing at the ability of cells to home to all bone compartments. Cortical and trabecular bone in the metaphysis undergoes more (re)modeling than the diaphysis (21) or the epiphysis (20). ...
Breast cancer often metastasizes to bone, causing osteolytic lesions. Structural and biophysical changes are rarely studied yet are hypothesized to influence metastasis. We developed a mouse model of early bone metastasis and multimodal imaging to quantify cancer cell homing, bone (re)modeling, and onset of metastasis. Using tissue clearing and three-dimensional (3D) light sheet fluorescence microscopy, we located enhanced green fluorescent protein–positive cancer cells and small clusters in intact bones and quantified their size and spatial distribution. We detected early bone lesions using in vivo microcomputed tomography (microCT)–based time-lapse morphometry and revealed altered bone (re)modeling in the absence of detectable lesions. With a new microCT image analysis tool, we tracked the growth of early lesions over time. We showed that cancer cells home in all bone compartments, while osteolytic lesions are only detected in the metaphysis, a region of high (re)modeling. Our study suggests that higher rates of (re)modeling act as a driver of lesion formation during early metastasis.
... Taq1 and Bsm1 have been associated with higher systemic vitamin D levels [24]. In addition, these SNPs were reported to be related to bone mineral density [25], which has mechanistically been correlated to reactivation of dormant tumor cells in bone [26,27]. Therefore, these four VDR SNPs were selected as candidate SNPs in our study. ...
Purpose
Vitamin D has some anticancer properties that may decrease breast cancer risk and improve prognosis. The aim was to investigate associations between four previously studied VDR SNPs (Taq1, Tru91, Bsm1, and Fok1) and prognosis in different groups of breast cancer patients.
Methods
VDR genotyping of 1,017 breast cancer patients included 2002–2012 in Lund, Sweden, was performed using Oncoarray. Follow-up was until June 30, 2019. Clinical data and patient information were collected from medical records and questionnaires. Cox regression was used for survival analyses.
Results
Genotype frequencies were as follows: Fok1 (AA 15.7%, AG 49.1%, GG 35.1%), Bsm1 (CC 37.2%, CT 46.1%, TT 16.7%), Tru91 (CC 77.8%, CT 20.7%, TT 1.5%), and Taq1 (AA 37.2%, AG 46.2%, GG 16.6%). During follow-up there were 195 breast cancer events. The homozygous variants of Taq1 and Bsm1 were associated with reduced risk of breast cancer events (adjusted HR = 0.59, 95% CI 0.38–0.92 for Taq1 and adjusted HR = 0.61, 95% CI 0.40–0.94 for Bsm1). The G allele of the Fok1 was associated with increased risk of breast cancer events in small tumors (pT1, adjusted HR = 1.83, 95% CI 1.04–3.23) but not in large tumors (pT2/3/4, adjusted HR = 0.80, 95% CI 0.41–1.59) with a borderline interaction (Pinteraction = 0.058). No interactions between VDR genotypes and adjuvant treatments regarding breast cancer prognosis were detected.
Conclusion
VDR genotypes were associated with breast cancer prognosis and the association might be modified by tumor size. Further research is needed to confirm the findings and elucidate their potential clinical implications.
... dormant cells can reactivate and proliferate, leading to metastasis and recurrence. [7][8][9] Polyploid giant cancer cells (PGCCs) contribute to tumour heterogeneity and play essential roles in tumour progression. 10 The number of PGCCs is relevant to tumour grade, lymph node metastasis, recurrence, chemoresistance and poor prognosis. ...
Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.
... In this context, osteoclasts have been described to reactivate multiple myeloma dormant cells. For example, the activation of osteoclasts by RANKL induces bone resorption, a process that can reactivate and release dormant tumor cells from the endosteal niche [140]. There is evidence that TAM receptors can function as a molecular switch between dormant and proliferative states in prostate cancer cells depending on cell-intrinsic TAM receptor expression. ...
The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis.
... More importantly, NCX1 induced calcium in ux of MM cells promoted RANKL-induced osteoclast differentiation [15]. Studies have con rmed that the BM microenvironment, especially BM osteoclasts, play a central role in supporting MM cell survival and drug resistance [19,20]. It is unclear whether NCX1 can affect the BTZ sensitivity of MM through osteoclasts. ...
... It is well known that cellular calcium homeostasis and autophagy play important roles in BTZ sensitivity of MM cells [23,24]. Our previous studies showed that extracellular calcium ([Ca 2+ ] o ) can activate NCX1, promote extracellular calcium in ux, and increase the viability of MM cells [19]. Here, we would like to further investigate the potential effects of high calcium microenvironment activating NCX1 expression on autophagy and BTZ sensitivity in MM cells. ...
Although bortezomib (BTZ) is the cornerstone of anti-multiple myeloma (MM) therapy, the inevitable primary and secondary drug resistance still seriously affects the prognosis of patients. New treatment strategies are in need. Sodium-calcium exchanger 1 (NCX1) is a calcium-permeable ion transporter on the membrane, and our previous studies showed that low NCX1 confers inferior viability in MM cells and suppressed osteoclast differentiation. However, the effect of NCX1 on BTZ sensitivity of MM and its possible mechanism remain unclear. In this study, we investigated the effect of NCX1 on BTZ sensitivity in MM, focusing on cellular processes of autophagy and cell viability. Our results provide evidence that NCX1 expression correlates with MM disease progression and low NCX1 expression increases BTZ sensitivity. NCX1/Ca ²⁺ triggered autophagic flux through non-canonical NFκB pathway in MM cells, leading to attenuated the sensitivity of BTZ. Knockdown or inhibition of NCX1 could potentiate the anti-MM activity of BTZ in vitro and vivo, and inhibition of autophagy sensitized NCX1-overexpressing MM cells to BTZ. In general, this work implicates NCX1 as a potential therapeutic target in MM with BTZ resistance and provides novel mechanistic insights into its vital role in combating BTZ resistance.
... This niche plays a pivotal role in the induction of MM dormancy [142,143], a state of quiescent growth arrest that allows MM cells to become unavailable to anti-myeloma therapy. Here, osteoblastic cells may control dormancy induction, while osteoclastic bone remodeling may promote dormancy escape and consequent disease relapse [144]. These residual MM cells accumulate mutations over time, driving later disease relapses and resulting in the incurable disease that is MM; thus, targeting myeloma bone disease may ultimately pose an effective avenue towards disease cure. ...
Simple Summary
Multiple myeloma is the second most common hematological malignancy, and the majority of patients have osteolytic lesions by the time of diagnosis. Bone destruction increases the risk of fractures and spinal cord compression, reduces quality of life, and is associated with increased mortality. This paper focuses on current and novel medical and surgical treatment modalities and improvements in prevention and the treatment of therapy-related complications, in particular, medication-related osteonecrosis of the jaw. A special focus reviews new promising targets in the bone marrow microenvironment.
Abstract
Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60–85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.
... Building on MoSaicNet, a new autoencoder-based approach was developed to study bone physiology. This was inspired by the potential role of bone and related cells, such as osteoblasts and osteoclasts, in regulating BM remodelling [14][42] and MM dormancy and proliferation [43]. Autoencoder is an effective method for dimension reduction and denoising. ...
Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphologic, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an AUC of >0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and posttreatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of patients with multiple myeloma, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and regulatory T cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of patients with multiple myeloma. In summary, deep learning–based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques.
Significance
Spatial analysis of bone marrow trephine biopsies using histology, deep learning, and tailored algorithms reveals the bone marrow architectural heterogeneity and evolution during myeloma progression and treatment.
