PXD050157-1

PXD050157 is an original dataset announced via ProteomeXchange.

Title	KRAS mutation-selective requirement for ACSS2 in colorectal adenoma formation
Description	Oncogenic KRAS mutations are prevalent in colorectal cancer (CRC) and are associated with poor prognosis and resistance to therapy. There is a substantial diversity of KRAS mutant alleles observed in CRC. Emerging clinical and experimental analysis of common KRAS mutations suggest that each mutation differently influences the clinical properties of a disease and response to therapy. Although there is some evidence to suggest biological differences between mutant KRAS alleles, these are yet to be fully elucidated. One approach to study allelic variation involves the use of isogenic cell lines that express different endogenous Kras mutants. Here, we generated Kras isogenic Apc-/- mouse colon epithelial cell lines using CRISPR-driven genome editing by altering the original G12D Kras allele to G12V, G12R, or G13D. We utilized these cell lines to perform transcriptomic and proteomic analysis to compare different signaling properties between these mutants. Both screens indicate significant differences in pathways relating to cholesterol and lipid regulation that we validated with targeted metabolomic measurements and isotope tracing. We found that these processes are upregulated in G12V lines through increased expression of nuclear SREBP1 and higher activation of mTORC1. G12V cells showed higher expression of ACSS2 and ACSS2 inhibition sensitized G12V cells to MEK inhibition. Finally, we found that ACSS2 plays a crucial role early in the development of G12V mutant tumors, in contrast to G12D mutant tumors. These observations highlight differences between KRAS mutant cell lines in their signaling properties. Further exploration of these pathways may prove to be valuable for understanding how specific KRAS mutants function, and identification of novel therapeutic opportunities in CRC.
HostingRepository	PRIDE
AnnounceDate	2025-05-02
AnnouncementXML	Submission_2025-05-02_08:27:14.505.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Chernoff
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-26 11:21:39	ID requested
⏵ 1	2025-05-02 08:27:15	announced

10.1016/j.celrep.2025.115444;

Budagyan K, Cannon AC, Chatoff A, Benton D, Kurimchak AM, Araiza-Olivera D, Gerasimova A, Snyder NW, Duncan JS, Uribe-Alvarez C, Chernoff J, KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation. Cell Rep, 44(4):115444(2025) [pubmed]

submitter keyword: Colorectal Cancer,KRAS, ACSS2

Jonathan Chernoff
contact affiliation	Cancer Signaling & Microenvironment Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States
contact email	J_Chernoff@fccc.edu
lab head
Jonathan Chernoff
contact affiliation	Fox Chase Cancer Center
contact email	J_Chernoff@fccc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050157
     1. Label: PRIDE project
     2. Name: KRAS mutation-selective requirement for ACSS2 in colorectal adenoma formation