Summary of Study ST002083

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001309. The data can be accessed directly via it's Project DOI: 10.21228/M8HH60 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study ID	ST002083
Study Title	Time-Resolved Metabolomics of a Mouse Model of High-Grade Serous Ovarian Cancer (MSI)
Study Summary	The dismally low survival rate of ovarian cancer patients diagnosed with high-grade serous carcinoma (HGSC) emphasizes the lack of effective screening strategies. One major obstacle is the limited knowledge of the underlying mechanisms of HGSC pathogenesis at very early stages. Here, we present the first 10-month time-resolved serum metabolic profile of a triple mutant (TKO) HGSC mouse model, along with the spatial lipidome profile of its entire reproductive system. A high-coverage liquid chromatography mass spectrometry-based metabolomics approach was applied to longitudinally collected serum samples from both TKO and TKO control mice, tracking metabolome and lipidome changes from disease onset until mouse death. Spatial lipid distributions within the reproductive system were also mapped via ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and compared with serum lipid profiles for various lipid classes. Altogether, our results show that the remodeling of lipid and fatty acid metabolism, amino acid biosynthesis, TCA cycle and ovarian steroidogenesis are critical components of HGSC onset and development. These metabolic alterations are accompanied by changes in energy metabolism, mitochondrial and peroxisomal function, redox homeostasis, and inflammatory response, collectively supporting tumorigenesis.
Institute	Georgia Institute of Technology
Department	School of Chemistry & Biochemistry
Laboratory	Facundo M. Fernandez
Last Name	Sah
First Name	Samyukta
Address	School of Chemistry & Biochemistry, 901 Atlantic Dr
Email	ssah9@gatech.edu
Phone	5746780124
Submit Date	2022-02-10
Raw Data Available	Yes
Analysis Type Detail	MALDI-MS
Release Date	2022-02-22
Release Version	1

Select appropriate tab below to view additional metadata details:

Project:

Project ID:	PR001309
Project DOI:	doi: 10.21228/M8HH60
Project Title:	Time-Resolved Metabolomics of a Mouse Model of Ovarian High-Grade Serous Carcinoma .
Project Type:	Untargeted serum metabolomics and mass spectrometry imaging
Project Summary:	The dismally-low survival rate of ovarian cancer patients diagnosed with high-grade serous carcinoma (HGSC) emphasizes the lack of effective screening strategies. One major obstacle is the limited knowledge of the underlying mechanisms of HGSC pathogenesis at very early stages. Here, we present the first 10-month time-resolved serum metabolic profile of a triple mutant (TKO) HGSC mouse model, along with the spatial lipidome profile of its entire reproductive system. A high-coverage liquid chromatography mass spectrometry-based metabolomics approach was applied to longitudinally-collected serum samples from both TKO and TKO control mice, tracking metabolome and lipidome changes from disease onset until death. Spatial lipid distributions within the reproductive system were also mapped via ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, and compared with serum lipid profiles for various lipid classes. Altogether, our results show that the remodeling of lipid and fatty acid metabolism, amino acid biosynthesis, TCA cycle and ovarian steroidogenesis are critical components of HGSC onset and development. These metabolic alterations are accompanied by changes in energy metabolism, mitochondrial and peroxisomal function, redox homeostasis, and inflammatory response, collectively supporting tumorigenesis.
Institute:	Georgia Institute of Technology
Department:	Chemistry and Biochemistry
Last Name:	Sah
First Name:	Samyukta
Address:	901 Atlantic Dr NE, Atlanta, GA, 30332, USA
Email:	ssah9@gatech.edu
Phone:	574-678-0124

Subject:

Subject ID:	SU002167
Subject Type:	Mammal
Subject Species:	Mus musculus
Taxonomy ID:	10090
Gender:	Female

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id	local_sample_id	Phenotype
SA198298	C1_17	Control
SA198299	T6_10	TKO

Showing results 1 to 2 of 2

Showing results 1 to 2 of 2

Collection:

Collection ID:	CO002160
Collection Summary:	Blood samples were collected from 17 TKO mice and 16 TKO control mice starting at 8 weeks of age. A sequential blood sampling procedure was conducted and samples from each mouse were collected every two weeks until end point or ascites. Two TKO mice died after 14 and 16 weeks, and were not included in the UHPLC-MS analysis. One TKO control mouse died after 10 weeks and was also excluded. For imaging experiments, TKO mice were sacrificed at advanced cancer stages, their reproductive systems collected and stored at -80 oC for tissue embedding and sectioning.
Sample Type:	Ovary

Treatment:

Treatment ID:	TR002179
Treatment Summary:	p53LSL R172H/+ Dicer1flox/flox Ptenflox/flox Amhr2cre/+ mice were generated by mating p53LSL-R172H/+Dicer1flox/floxPtenflox/flox female mice with Dicer1flox/floxPtenflox/floxAmhr2cre/+ male mice. p53LSL-R172H/+Dicer1flox/floxPtenflox/flox mice were used as TKO controls (ctrl). TKO ctrl mice carry the same genetic background as TKO mice but do not develop HGSC. p53LSL R172H/+ Dicer1flox/flox Ptenflox/flox Amhr2cre/+ mice were sacrificed in accordance to the animal protocol approved by the institutional animal care and use committee (IACUC) at Indiana University.

Treatment ID:

TR002179

Treatment Summary:

p53LSL R172H/+ Dicer1flox/flox Ptenflox/flox Amhr2cre/+ mice were generated by mating p53LSL-R172H/+Dicer1flox/floxPtenflox/flox female mice with Dicer1flox/floxPtenflox/floxAmhr2cre/+ male mice. p53LSL-R172H/+Dicer1flox/floxPtenflox/flox mice were used as TKO controls (ctrl). TKO ctrl mice carry the same genetic background as TKO mice but do not develop HGSC. p53LSL R172H/+ Dicer1flox/flox Ptenflox/flox Amhr2cre/+ mice were sacrificed in accordance to the animal protocol approved by the institutional animal care and use committee (IACUC) at Indiana University.

Sample Preparation:

Sampleprep ID:	SP002173
Sampleprep Summary:	For MS imaging experiments, TKO mice were sacrificed at advanced cancer stages, their reproductive systems collected and stored at -80 oC. Following examination of a variety of tissue samples, we focused on a TKO mouse reproductive system that showed a HGSC on one of the fallopian tubes, with the healthy ovary engulfed in the tumor and adjacent cysts. In this tissue sample, the HGSC region connects with the opposite healthy ovary and fallopian tube through the uterus. These freshly frozen tissues were embedded in an aqueous solution containing 1 % CMC and 5 % (by weight) gelatin. Tissue embedding was conducted in an isopentane-dry ice bath at -20 oC. A CryoStar NX70 Cryostat was used for cryosectioning. The sectioning temperature was set to -20 oC and each slice was sectioned at a thickness of 10 µm. Sectioned tissue slices were transferred to Fisherbrand™ Superfrost™ Plus microscope slides for MALDI imaging MS experiments. Mounted tissue slices were sprayed with 5 mg mL-1 1,5-DAN prior to MALDI MS. 1,5-DAN was dissolved in 65/20/15 (v/v/v) acetonitrile/methanol/chloroform and sprayed via an iMatrix matrix sprayer. The sprayer nozzle height was set to 60 mm, the speed of the nozzle movement was 200 mm s-1. The inter-line distance was 1 mm. One µL of the matrix solution was sprayed onto an area of 1 cm2 on average. The spray cycle was repeated 10 times to ensure complete and uniform matrix coverage on tissue sections. A Bruker SolariX 12-Tesla Fourier-transform ion cyclotron resonance (FTICR) mass spectrometer equipped with a MALDI ion source was used for all spatial lipidomics imaging experiments. The mass spectrometer was operated in the negative ion mode for fatty acid and lipid feature discovery in the 150–1200 m/z range. The laser power was set to 25%, and the number of laser shots accumulated on each pixel was 300. The laser repetition frequency was 1000 Hz, and the laser beam focus size was set to minimum. The spatial resolution defined by the pixel size of the images was 50 µm × 50 µm. The time domain data set size was set to 4,000,000, corresponding to a mass resolution of 410,000 at m/z 400, and the FID transient time was 0.4194 s. The mass spectrometer was calibrated externally with (+)ESI and (-)ESI CalMix solution and internally with FA(18:1) and PI(38:4) to ensure mass accuracy was better than 1 ppm on average. Observed ions in the average mass MALDI spectrum were subject to Lipid Maps and HMDB database searches using METASPACE. Features with a false discovery rate of 10% or less were chosen and compared to features annotated in LC-MS serum studies.

Sampleprep ID:

SP002173

Sampleprep Summary:

For MS imaging experiments, TKO mice were sacrificed at advanced cancer stages, their reproductive systems collected and stored at -80 oC. Following examination of a variety of tissue samples, we focused on a TKO mouse reproductive system that showed a HGSC on one of the fallopian tubes, with the healthy ovary engulfed in the tumor and adjacent cysts. In this tissue sample, the HGSC region connects with the opposite healthy ovary and fallopian tube through the uterus. These freshly frozen tissues were embedded in an aqueous solution containing 1 % CMC and 5 % (by weight) gelatin. Tissue embedding was conducted in an isopentane-dry ice bath at -20 oC. A CryoStar NX70 Cryostat was used for cryosectioning. The sectioning temperature was set to -20 oC and each slice was sectioned at a thickness of 10 µm. Sectioned tissue slices were transferred to Fisherbrand™ Superfrost™ Plus microscope slides for MALDI imaging MS experiments. Mounted tissue slices were sprayed with 5 mg mL-1 1,5-DAN prior to MALDI MS. 1,5-DAN was dissolved in 65/20/15 (v/v/v) acetonitrile/methanol/chloroform and sprayed via an iMatrix matrix sprayer. The sprayer nozzle height was set to 60 mm, the speed of the nozzle movement was 200 mm s-1. The inter-line distance was 1 mm. One µL of the matrix solution was sprayed onto an area of 1 cm2 on average. The spray cycle was repeated 10 times to ensure complete and uniform matrix coverage on tissue sections. A Bruker SolariX 12-Tesla Fourier-transform ion cyclotron resonance (FTICR) mass spectrometer equipped with a MALDI ion source was used for all spatial lipidomics imaging experiments. The mass spectrometer was operated in the negative ion mode for fatty acid and lipid feature discovery in the 150–1200 m/z range. The laser power was set to 25%, and the number of laser shots accumulated on each pixel was 300. The laser repetition frequency was 1000 Hz, and the laser beam focus size was set to minimum. The spatial resolution defined by the pixel size of the images was 50 µm × 50 µm. The time domain data set size was set to 4,000,000, corresponding to a mass resolution of 410,000 at m/z 400, and the FID transient time was 0.4194 s. The mass spectrometer was calibrated externally with (+)ESI and (-)ESI CalMix solution and internally with FA(18:1) and PI(38:4) to ensure mass accuracy was better than 1 ppm on average. Observed ions in the average mass MALDI spectrum were subject to Lipid Maps and HMDB database searches using METASPACE. Features with a false discovery rate of 10% or less were chosen and compared to features annotated in LC-MS serum studies.

Combined analysis:

Analysis ID	AN003400
Analysis type	MS
Chromatography type	None (Direct infusion)
Chromatography system	none
Column	none
MS Type	MALDI
MS instrument type	FT-ICR
MS instrument name	Bruker Solarix FT-ICR-MS
Ion Mode	NEGATIVE
Units	mass peak abundances

Chromatography:

Chromatography ID:	CH002513
Instrument Name:	none
Column Name:	none
Chromatography Type:	None (Direct infusion)

MS:

MS ID:	MS003167
Analysis ID:	AN003400
Instrument Name:	Bruker Solarix FT-ICR-MS
Instrument Type:	FT-ICR
MS Type:	MALDI
MS Comments:	Data processed by SCiLS Lab Core 2021c, features assigned by METASPACE database
Ion Mode:	NEGATIVE