TY - UNPB
T1 - Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations
AU - Yan, Hong
AU - Talty, Ronan
AU - Jain, Abhishek
AU - Cai, Yuping
AU - Zheng, Jie
AU - Shen, Xinyi
AU - Muca, Engjel
AU - Paty, Philip B.
AU - Bosenberg, Marcus W.
AU - Khan, Sajid A.
AU - Johnson, Caroline H.
N1 - This research was funded by NIH 1R21CA223686-01 (C.H.J., S.A.K.) and American Cancer Society research scholar grant 134273-RSG-20-065-01-TBE (C.H.J.). C.H.J would also like to acknowledge support from the National Cancer Institute of the NIH under Award Number K12CA215110, the NIH/NCI Yale SPORE in Skin Cancer under award number 5P50CA121974. RT is supported by NIH/NCI F30CA254246. This publication was also made possible by CTSA grant number UL1 TR001863 from the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), NIH roadmap for Medical Research, and Women’s Health Research at Yale. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. This work was also supported by the Lampman Research Fund in Yale Surgical Oncology. R.T. is supported by NIH F30CA254246.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.
AB - Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.
KW - KRAS
KW - colorectal cancer
KW - ferroptosis
KW - sex-specific differences
KW - metabolomics
U2 - 10.1101/2023.02.28.530478
DO - 10.1101/2023.02.28.530478
M3 - Preprint
T3 - bioRxiv
SP - 1
EP - 40
BT - Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations
PB - Cold Spring Harbor Laboratory
ER -
SDG 3 Good Health and Well-being