Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

Damaghi, Mehdi; Gillies, Robert J.

doi:10.1080/15384101.2016.1231284

Cited by 56 publications

(51 citation statements)

References 18 publications

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“…Moreover, the acidic environment of solid tumors has recently been proposed to provide a niche for dormant cells based on these features [24]. The present study showed that the acid-adapted SW620 cells have stronger tumorigenicity in subcutaneous transplantation model, which is consistent with a previous study showing that the acid adapted breast cancer cells grow faster in vivo [17]. In addition to higher proliferating index, the SW620-AA-originated tumors showed high expression of CA9, reflecting more acidic areas in these tumors.…”

Section: Discussionsupporting

confidence: 92%

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Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

et al. 2019

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Song He (2019) Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells, Cell Cycle, 18:4, 511-522, ABSTRACTThe acidic extracellular microenvironment, namely acidosis, is a biochemical hallmark of solid tumors. However, the tumorigenicity, metastatic potential, gene expression profile and chromatin accessibility of acidosis-adapted colorectal cancer cells remain unknown. The colorectal cancer cell SW620 was cultured in acidic medium (pH 6.5) for more than 3 months to be acidosis-adapted (SW620-AA). In comparison to parental cells, SW620-AA cells exhibit enhanced tumorigenicity and liver metastatic potential in vivo. Following mRNA and lncRNA expression profiling, we validated that OLMF1, NFIB, SMAD9, DGKB are upregulated, while SESN2, MAP1B, UTRN, PCDH19, IL18, LMO2, CNKSR3, GXYLT2 are downregulated in SW620-AA cells. The differentially expressed mRNAs were significantly enriched in DNA remodeling-associated pathways including HDACs deacetylate histones, SIRT1 pathway, DNA methylation, DNA bending complex, and RNA polymerase 1 chain elongation. Finally, chromatin accessibility evaluation by ATAC-sequencing revealed that the differentially opened peaks were enriched in pathways such as small cell lung cancer, pathways in cancer, ErbB signaling, endometrial cancer, and chronic myeloid leukemia, which were mainly distributed in intergenic regions and introns. These results suggest that the chromatin accessibility changes are correlated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 92%

“…The acidic-adapted pancreatic cancer cells also tend to take advantage of glutamine to fuel the respiration [16]. Furthermore, it has been reported that the acid-adapted breast cancer cells grow faster in vivo and exhibit invasive phenotype [17].…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

et al. 2019

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“…It’s been known for more than a decade that the center of the ducts in solid cancer models such as breast or prostate cancer is one of the most acidic habitats in the whole tumor ecosystem (Fig 1A) (3, 4, 35). Mechanisms, allowing tumor cells to tolerate acidosis have been studied extensively by our group (4, 36, 37) and others (36, 38).…”

Section: Resultsmentioning

confidence: 99%

Collagen Production and Niche Engineering: A Novel Strategy for Cancer Cells to Survive Acidosis and Evolve

Damaghi

Byrne

et al. 2019

Preprint

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Ductal Carcinoma in situ (DCIS) is an avascular disease characterized by profound acidosis. Premalignant cells within this niche must adapt to acidosis to survive and thrive. A component of this acidadaptation involves extracellular matrix remodeling leading to niche construction and remodeling.Using discovery proteomics, we identified that collagen producing enzyme PLODs are upregulated in acid-adapted breast cancer cells. Second harmonic generation microscopy showed significant collagen deposition within DCIS lesions of patients. In vitro analyses identified that acid-adaptation involves production of rare collagens that can be regulated by Ras and SMAD pathway. Secretome analysis showed upregulation ECM remodeling enzymes such as TGM2 and LOXL2. Comparison of acid induced collagens in vitro and in patient data showed correlation between rare collagens production and survival of patients. We conclude acidosis induces collagen production by cancer cells and promote growth independent of basal membrane attachment. The independently produced collagen can be used for niche construction and engineering as an adaptation strategy of cancer cells to survive and evolve.

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“…Assays were conducted in 3D spheroid cultures with varying starting frequencies of each cell type. The spheroid system was selected as an in vitro intermediate between 2D cell culture, which may reach an equilibrium state through confluence rather than resource competition, and in vivo subcutaneous mouse models, which provide less opportunity for replication and frequent monitoring of the two cell populations (27–34). Spheroids were grown in various combinations of pH and glucose concentrations, letting the 3D structure provide natural nutrient and oxygen gradients.…”

Section: Introductionmentioning

confidence: 99%

Frequency-dependent interactions determine outcome of competition between two breast cancer cell lines

Freischel

Damaghi

Cunningham

et al. 2020

Preprint

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Highlights: 15 • Demonstrate how mixed-culture spheroids must be used to characterize competition 16 between two cancer cell lines. 17 • Competition alters growth dynamics of cancer cells. 18 • Competition growth models can be used to quantify density-independent, density-19 dependent and frequency-dependent effects on competition. 20 • Competition affects tumor progression and structure, making it key to understanding 21 tumor development and evolution. 22 ABSTRACT: 23Tumors are highly dynamic ecosystems in which diverse cancer cell subpopulations compete for space 24 and resources. These complex, often non-linear interactions govern continuous spatial and temporal 25 changes in the size and phenotypic properties of these subpopulations. Because intra-tumoral blood 26 flow is often chaotic, competition for resources may be a critical selection factor in progression and 27 prognosis. Here, we quantify resource competition using 3D spheroid cultures with MDA-MB-231 and 28 MCF-7 breast cancer cells. We hypothesized that MCF-7 cells, which primarily rely on efficient aerobic 29 glucose metabolism, would then dominate the population under normoxic conditions; and MDA-MB-30 231 cells, which exhibit high levels of glycolytic metabolism, would dominate under hypoxic conditions. 31In spheroids with single populations, MCF-7 cells exhibited equal or superior intrinsic growth rates 32 (density-independent measure of success) and carrying capacities (density-dependent measure of 33 success) when compared to MDA-MB-231 cells in both normoxic and hypoxic conditions. However, 34 when the populations were mixed, MDA-MB-231 cells outcompeted MCF-7 cells under all conditions 35 with competition dynamics determined by frequency-dependent interactions. When grown together, 36 MDA-MB-231 suffered little from MCF-7 while MCF-7 cells experienced a disproportionately large 37 reduction in growth rates in the presence of MDA-MB-231 cells. We frame these results in a game-38 theoretic (frequency-dependent) model of cancer cell interactions and conclude that competition assays 39 can demonstrate critical density-independent, density-dependent and frequency-dependent 40 interactions that likely contribute to in vivo outcomes. 41Key Words: cancer cell competition, tumor ecology, tumor evolution, evolutionary therapy 42 43 INTRODUCTION: 44Each malignant tumor typically contains diverse and heterogeneous habitats due to spatial and temporal 45 variations in cell density, immune infiltration, and blood flow (1-3). Here, we investigate the 46 evolutionary effects of variations in substrate (e.g. glucose, oxygen, and glutamine) and metabolites 47Recently, two general "niche construction" strategies were observed in clinical and pre-clinical cancers 51 (4, 5). The first consists of cancer cells that possess high levels of aerobic glycolysis that generate an 52 acidic environment which promotes invasion and protects cells from the immune system. These cells are 53 typically invasive and motile. In the second niche construction strat...

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Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

Cited by 56 publications

References 18 publications

Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

Collagen Production and Niche Engineering: A Novel Strategy for Cancer Cells to Survive Acidosis and Evolve

Frequency-dependent interactions determine outcome of competition between two breast cancer cell lines

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