Summary of Study ST003102
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 PR001925. The data can be accessed directly via it's Project DOI: 10.21228/M8WM7T 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.
| Study ID | ST003102 |
| Study Title | Cellular adaptation to cancer therapy along a resistance continuum |
| Study Summary | Recent research has shed light on the role of non-genetic plasticity in transient drug tolerance and the acquisition of stable resistance. However, the dynamics of cell state transitions occurring in the adaptation to cancer therapies remain elusive and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell state transitions accompanied by a progressive increase in cell fitness, which we denote the ‘resistance continuum’. This cellular adaptation involves a step-wise assembly of gene expression programs and epigenetically reinforced cell states underpinned by phenotypic plasticity stress adaptation and metabolic reprogramming. Through systematic genetic perturbations, we identify an acquisition of progressive metabolic dependencies, exposing a spectrum of vulnerabilities that can be potentially exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell state transitions. |
| Institute | NYU Langone Health |
| Last Name | Starvaggi Franca |
| First Name | Gustavo |
| Address | 430 East 29th Street, NY NY 10016 |
| Gustavo.StarvaggiFranca@nyulangone.org | |
| Phone | 6465015151 |
| Submit Date | 2024-02-13 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzXML |
| Analysis Type Detail | LC-MS |
| Release Date | 2024-04-02 |
| Release Version | 1 |
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Project:
| Project ID: | PR001925 |
| Project DOI: | doi: 10.21228/M8WM7T |
| Project Title: | Cellular adaptation to cancer therapy along a resistance continuum |
| Project Summary: | Recent research has shed light on the role of non-genetic plasticity in transient drug tolerance and the acquisition of stable resistance. However, the dynamics of cell state transitions occurring in the adaptation to cancer therapies remain elusive and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell state transitions accompanied by a progressive increase in cell fitness, which we denote the ‘resistance continuum’. This cellular adaptation involves a step-wise assembly of gene expression programs and epigenetically reinforced cell states underpinned by phenotypic plasticity stress adaptation and metabolic reprogramming. Through systematic genetic perturbations, we identify an acquisition of progressive metabolic dependencies, exposing a spectrum of vulnerabilities that can be potentially exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell state transitions. |
| Institute: | NYU Langone Health |
| Last Name: | Starvaggi Franca |
| First Name: | Gustavo |
| Address: | 430 E 29th Street |
| Email: | Gustavo.StarvaggiFranca@nyulangone.org |
| Phone: | 646-501-4603 |
| Funding Source: | NIH grants: P50 CA225450 |
Subject:
| Subject ID: | SU003217 |
| Subject Type: | Cultured cells |
| Subject Species: | Homo sapiens |
| Taxonomy ID: | 9606 |
| Species Group: | Mammals |
Factors:
Subject type: Cultured cells; Subject species: Homo sapiens (Factor headings shown in green)
| mb_sample_id | local_sample_id | Treatment |
|---|---|---|
| SA333491 | S25059 | C |
| SA333492 | S25061 | C |
| SA333493 | S25060 | C |
| SA333494 | S25064 | C_drug |
| SA333495 | S25062 | C_drug |
| SA333496 | S25063 | C_drug |
| SA333497 | S25067 | T320 |
| SA333498 | S25065 | T320 |
| SA333499 | S25066 | T320 |
| SA333500 | S25070 | T320_drug |
| SA333501 | S25069 | T320_drug |
| SA333502 | S25068 | T320_drug |
| Showing results 1 to 12 of 12 |
Collection:
| Collection ID: | CO003210 |
| Collection Summary: | To generate drug-induced PARPi resistant populations, 1×106 Kuramochi drug-naïve cells (C) were initially seeded in 150 mm plates. |
| Sample Type: | Ovarian cancer cells |
Treatment:
| Treatment ID: | TR003226 |
| Treatment Summary: | Twenty four hours after seeding, 1 uM of olaparib (Selleckchem, S1060) was added and cells were maintained under treatment until reaching confluency (> 70%), thus characterizing resistance at this dose. Cells were harvested (0.25% Trypsin/EDTA for 5 min at 37°C) and a fraction of the surviving population (1×106 cells) was seeded again and treated with 2.5 uM until cells reached confluency. This process was repeated sequentially by doubling the drug concentrations until the cell populations were able to achieve confluency at 320 uM of olaparib (T320). The initial dose was determined by cell viability assays, indicating a low starting dose (< IC30). At each step, aliquots of the adapted populations were frozen (10% DMSO, 50% FBS, 40% media) for further experiments |
Sample Preparation:
| Sampleprep ID: | SP003223 |
| Sampleprep Summary: | Kuramochi cells (C and T320) were cultured until ~80% confluence either on 320 uM of olaparib for 24h or off treatment in triplicates per condition. Cell pellets were collected and frozen with liquid nitrogen for submission to the NYU Metabolomics Core Resource Laboratory. Samples were subjected to an LCMS analysis to detect and quantify known peaks. A metabolite extraction was carried out on each sample based on a previously described method116. |
Chromatography:
| Chromatography ID: | CH003833 |
| Methods Filename: | L12 |
| Chromatography Comments: | The LC column was a MilliporeTM ZIC-pHILIC (2.1 x150 mm, 5 μm) coupled to a Dionex Ultimate 3000TM system and the column oven temperature was set to 25oC for the gradient elution. A flow rate of 100 μL/min was used with the following buffers; A) 10 mM ammonium carbonate in water, pH 9.0, and B) neat acetonitrile. The gradient profile was as follows; 80-20%B (0-30 min), 20-80%B (30-31 min), 80-80%B (31-42 min). Injection volume was set to 2 μL for all analyses (42 min total run time per injection). |
| Instrument Name: | Ulitmate 3000 |
| Column Name: | SeQuant ZIC-pHILIC (150 x 4.6mm,5um) |
| Column Pressure: | 1800 |
| Column Temperature: | 25 |
| Flow Gradient: | 80-20%B (0-30 min), 20-80%B (30-31 min), 80-80%B (31-42 min) |
| Flow Rate: | 0.1mL/min |
| Injection Temperature: | 4 |
| Internal Standard: | ISTD (500nM amino acid cocktail) |
| Sample Injection: | 2uL |
| Solvent A: | 100% water; 10 mM ammonium carbonate, pH 9.0 |
| Solvent B: | 100% acetonitrile |
| Analytical Time: | 30m |
| Oven Temperature: | 28 |
| Chromatography Type: | HILIC |
Analysis:
| Analysis ID: | AN005076 |
| Analysis Type: | MS |
| Chromatography ID: | CH003833 |
| Num Factors: | 4 |
| Num Metabolites: | 147 |
| Units: | Arbitrary units |
