A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures

Clark, Amanda M.; Kumar, Manu P.; Wheeler, Sarah; Young, Carissa L.; Venkataramanan, Raman; Stolz, Donna B.; Griffith, Linda G.; Lauffenburger, Douglas A.; Wells, Alan

doi:10.1074/mcp.ra117.000370

Cited by 43 publications

(66 citation statements)

References 53 publications

(7 reference statements)

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“…SC-seq: Comparative transcriptomics to reveal senescent, stem-like, or dormant cells (Marlow and Dontu, 2015;Milanovic et al, 2018) 3. In vitro or ex vivo models: studying emergence of dormancy by ex vivo tissue culture models (Clark et al, 2018;Marlow and Dontu, 2015;Wheeler et al, 2014 understanding of cell polarity and the initiation of chemotaxis and invasion (Olivenç a et al, 2018). In this model, all species of the pathways are modeled, along with their spatial localization within the cell, suggesting strategies to control the activities of various molecular species within the pathway.…”

Section: Mechanistic Models Of Metastasis--toward Linking Mechanisms mentioning

confidence: 99%

“…Integration of data across scales, both not characterized by ''sequence information,'' is fraught with challenges that are more profound. Well-characterized phenotypes with richly defined feature sets could be mapped to transcriptomic, and genomic scales, e.g., characterizing tumor organoid shape and other characteristics for precision medicine, as well as RNA sequencing (Clark et al, 2018;Ewald, 2017). Tissue-level details can be integrated with transcriptomics by spatial single-cell RNA (scRNA) sequencing, for which more and more methods are being developed (Moncada et al, 2019;Stå hl et al, 2016).…”

Section: Integrating Models Of Metastasismentioning

confidence: 99%

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Systems Biology of Cancer Metastasis

et al. 2019

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Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon.

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Section: Mechanistic Models Of Metastasis--toward Linking Mechanisms mentioning

confidence: 99%

Section: Integrating Models Of Metastasismentioning

confidence: 99%

Systems Biology of Cancer Metastasis

et al. 2019

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“…LPS/EGF Inhibitor of immunologic dormancy Activated immune/stromal cells stimulate the resident hepatic cells to derive tumor growth. [9] Mitochondrial dysfunction Inhibitor of metabolic dormancy VLX600 impairs OXPHOS and drives a HIF-1α-dependent switch to glycolysis, which this metabolic pathway can't meet the energy demands of tumor cells, thus induction of autophagy is unavoidable. Yet, due to lack of HIF-1α-stabilization and glucose inaccessibility in metabolically stressed environments, shifting to glycolysis mode will be restricted, consequently, tumor cells undergo apoptosis.…”

Section: Inducer Of Immunologic Dormancymentioning

confidence: 99%

“…In tumor mass dormancy a stagnation of total tumor growth due to the equilibrium of proliferation and apoptosis is governed by an angiogenic switch or immune escape (two prevailing mechanisms) that eventually shifts the balance in favor of cancer progression [8]. Accordingly, current in vitro, in vivo and ex vivo (organs-on-a-chip) experimental models of cancer dormancy can mimic cellular and tumor mass dormancy (angiogenic and immunologic dormancy), each reflecting distinct growth kinetics [9]. These models were somewhat successful in recapitulating dormancy mechanism of tumors, as they lead to the discovery of cellular dormancy factors/mechanisms including extracellular matrix (ECM) [10], metabolic [11,12], epigenetic [13,14], stemness [15,16], non-coding RNAs [17], and p38 stress-induced signaling pathway [18][19][20], as we intend to discuss in detail in this review (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

Jahanban‐Esfahlan

Seidi

Manjili

et al. 2019

Cancers

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Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including angiogenic switch, immune escape, cancer stem cells, extracellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer and discuss the implications of such approaches in cancer treatment.

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“…Similarly, Akt was found as a factor supporting survival or outgrowth of BCCs in bone in vivo (Zhang et al, 2013) and in vitro (Korah et al, 2004) and in an in vitro model of lung . The proinflammatory cytokine LPS induces outgrowth of quiescent cells in lung (Cock et al, 2016;Albrengues et al, 2018) and in an in vitro model of dormancy in the liver (Clark et al, 2018).…”

Section: Organ-shared Mechanisms Of Dormancymentioning

confidence: 99%

In vitro Models of Breast Cancer Metastatic Dormancy

Montagner

2020

Front. Cell Dev. Biol.

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Delayed relapses at distant sites are a common clinical observation for certain types of cancers after removal of primary tumor, such as breast and prostate cancer. This evidence has been explained by postulating a long period during which disseminated cancer cells (DCCs) survive in a foreign environment without developing into overt metastasis. Because of the asymptomatic nature of this phenomenon, isolation, and analysis of disseminated dormant cancer cells from clinically disease-free patients is ethically and technically highly problematic and currently these data are largely limited to the bone marrow. That said, detecting, profiling and treating indolent metastatic lesions before the onset of relapse is the imperative. To overcome this major limitation many laboratories developed in vitro models of the metastatic niche for different organs and different types of cancers. In this review we focus specifically on in vitro models designed to study metastatic dormancy of breast cancer cells (BCCs). We provide an overview of the BCCs employed in the different organotypic systems and address the components of the metastatic microenvironment that have been shown to impact on the dormant phenotype: tissue architecture, stromal cells, biochemical environment, oxygen levels, cell density. A brief description of the organ-specific in vitro models for bone, liver, and lung is provided. Finally, we discuss the strategies employed so far for the validation of the different systems.Keywords: cancer dormancy, metastatic dormancy, in vitro models cancer, cancer metastasis, breast cancer, metastasis biology METASTATIC DORMANCYDormancy is an old concept that describes a clinical phenomenon (Klein, 2011; Uhr and Pantel, 2011), i.e., the relapse of a cancer after surgical removal of the primary tumor in a patient considered clinically disease-free for a long time. This implies that cancer cells disseminated prior to surgery and persisted as Minimal Residual Disease (MRD) for a prolonged time (arbitrarily defined, but usually longer than 5 years) before switching to aggressive growth and overt metastasis. The recurrence can be at the primary site (primary tumor dormancy) or at a secondary site (metastatic dormancy). The mechanisms underlying the two types of dormancy are likely to be partially overlapping if involving cell intrinsic genetic/epigenetic mechanisms, or distinct, if dependent on the tissue microenvironment. Clinical dormancy is common for breast, prostate, melanoma, renal, and thyroid cancers, while it is rarely observed in lung and colon cancers (Uhr and Pantel, 2011). In breast cancers, estrogen receptor (ER) status seems to profoundly influence the rate of relapse: ER− patients tend to recur within the first 5 years following primary tumor diagnosis, while ER+ patients have increased risk between 5 and 20 years (Pan et al., 2017;Pantel and Hayes, 2018). While anti-estrogen therapy significantly improved patient outcomes, a significant fraction of them still

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A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures

Cited by 43 publications

References 53 publications

Systems Biology of Cancer Metastasis

Systems Biology of Cancer Metastasis

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

In vitro Models of Breast Cancer Metastatic Dormancy

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