Visualization of Breast Cancer Metabolism Using Multimodal Nonlinear Optical Microscopy of Cellular Lipids and Redox State

Hou, Jue; Williams, Joshua; Botvinick, Elliot L.; Potma, Eric O.; Tromberg, Bruce J.

doi:10.1158/0008-5472.can-17-2618

Cited by 28 publications

(18 citation statements)

References 50 publications

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“…Fig. 2 ), and assessment of the optical redox ratio of the metabolic coenzymes FAD and NAD(P)H using multiphoton imaging [31] demonstrated a significant decrease in the FAD / [FAD + NAD(P)H] ratio with SIRT3 knock-down in anchorage-independent cells ( Fig. 3C ).…”

Section: Resultsmentioning

confidence: 99%

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim

Gupta-Vallur

Jones

et al. 2019

Preprint

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Cells must alter their antioxidant capacity for maximal metastatic potential. However, the antioxidant adaptations required for transcoelomic metastasis, which is the passive dissemination of cancer cells in the peritoneal cavity as seen in ovarian cancer, have largely remained unexplored. Contradicting the need for oxidant scavenging by tumor cells is the observation that expression of the nutrient stress sensor and regulator of mitochondrial antioxidant defenses, SIRT3, is suppressed in many primary tumors. We discovered that this mitochondrial deacetylase is however, upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase SOD2. This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent transcriptional increases in SOD2 during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 up-regulation and SIRT3-mediated oxidant scavenging following matrix detachment are required for anoikis resistance in vitro, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim

Gupta-Vallur

Jones

et al. 2019

Preprint

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“…Using CARS and SRS microscopy to specifically detect C-H bonds in FAs, we quantify lipid content per cell ( 45 ). Using this method, lipid abundances are measured as the number of pixels that belong to lipid droplets in a cell over the total pixel numbers of the entire cell ( 46 ).…”

Section: Resultsmentioning

confidence: 99%

Lipid remodeling in response to methionine stress in MDA-MBA-468 triple-negative breast cancer cells

Borrego

Fahrmann

Hou

et al. 2021

Journal of Lipid Research

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Methionine (Met) is an essential amino acid and critical precursor to the cellular methyl donor S-adenosylmethionine. Unlike nontransformed cells, cancer cells have a unique metabolic requirement for Met and are unable to proliferate in growth media where Met is replaced with its metabolic precursor, homocysteine. This metabolic vulnerability is common among cancer cells regardless of tissue origin and is known as "methionine dependence", "methionine stress sensitivity", or the Hoffman effect. The response of lipids to Met stress, however, is not wellunderstood. Using mass spectroscopy, label-free vibrational microscopy, and next-generation sequencing, we characterize the response of lipids to Met stress in the triple-negative breast cancer cell line MDA-MB-468 and its Met stress insensitive derivative, MDA-MB-468res-R8. Lipidome analysis identified an immediate, global decrease in lipid abundances with the exception of triglycerides and an increase in lipid droplets in response to Met stress specifically in MDA-MB-468 cells. Furthermore, specific gene expression changes were observed as a secondary response to Met stress in MDA-MB-468, resulting in a downregulation of fatty acid metabolic genes and an upregulation of genes in the unfolded protein response pathway. We conclude that the extensive changes in lipid abundance during Met stress is a direct consequence of the modified metabolic profile previously described in Met stress-sensitive cells. The changes in lipid abundance likely results in changes in membrane composition inducing the unfolded protein response we observe.Supplementary key words cancer metabolism • homocysteine • methionine • methionine stress • lipid metabolism • lipid droplets • phospholipids • fatty acid metabolism • triglycerides Methionine (Met) metabolism is an integral aspect in cellular function and is particularly important in cancer. Cancer cells that cannot proliferate in growth medium when Met is replaced with its metabolic precursor, homocysteine (Hcy), have been character-

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“…Additionally, a label-free imaging technique called non-linear optical microscopy (NLOM), has been studied for both precision and safety advantages. The principle of label-free non-linear optical microscopy is based on two-photon excited fluorescence (TPEF) from cofactors nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD + ) that provides high-resolution cellular redox imaging (Hou et al, 2018). More interestingly, this technique shares the same redox reactions to CL and UECL, therefore the two techniques could possibly image the tissues simultaneously and complement each other.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Ultrasound-Enhanced Chemiluminescence for Bioimaging

Dhamecha

Gonsalves

et al. 2020

Front. Bioeng. Biotechnol.

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Tissue imaging has emerged as an important aspect of theragnosis. It is essential not only to evaluate the degree of the disease and thus provide appropriate treatments, but also to monitor the delivery of administered drugs and the subsequent recovery of target tissues. Several techniques including magnetic resonance imaging (MRI), computational tomography (CT), acoustic tomography (AT), biofluorescence (BF) and chemiluminescence (CL), have been developed to reconstruct three-dimensional images of tissues. While imaging has been achieved with adequate spatial resolution for shallow depths, challenges still remain for imaging deep tissues. Energy loss is usually observed when using a magnetic field or traditional ultrasound (US), which leads to a need for more powerful energy input. This may subsequently result in tissue damage. CT requires exposure to radiation and a high dose of contrast agent to be administered for imaging. The BF technique, meanwhile, is affected by strong scattering of light and autofluorescence of tissues. The CL is a more selective and sensitive method as stable luminophores are produced from physiochemical reactions, e.g. with reactive oxygen species. Development of near infrared-emitting luminophores also bring potential for application of CL in deep tissues and whole animal studies. However, traditional CL imaging requires an enhancer to increase the intensity of low-level light emissions, while reducing the scattering of emitted light through turbid tissue environment. There has been interest in the use of focused ultrasound (FUS), which can allow acoustic waves to propagate within tissues and modulate chemiluminescence signals. While light scattering is decreased, the spatial resolution is increased with the assistance of US. In this review, chemiluminescence detection in deep tissues with assistance of FUS will be highlighted to discuss its potential in deep tissue imaging.

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Visualization of Breast Cancer Metabolism Using Multimodal Nonlinear Optical Microscopy of Cellular Lipids and Redox State

Cited by 28 publications

References 50 publications

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Lipid remodeling in response to methionine stress in MDA-MBA-468 triple-negative breast cancer cells

Ultrasound-Enhanced Chemiluminescence for Bioimaging

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