Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells
Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared wit...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2022
|
| Online Access: | https://hdl.handle.net/1721.1/138808 |
| _version_ | 1826197020787867648 |
|---|---|
| author | Schwartz, Andrew J Goyert, Joshua W Solanki, Sumeet Kerk, Samuel A Chen, Brandon Castillo, Cristina Hsu, Peggy P Do, Brian T Singhal, Rashi Dame, Michael K Lee, Ho-Joon Spence, Jason R Lakhal-Littleton, Samira Heiden, Matthew G Vander Lyssiotis, Costas A Xue, Xiang Shah, Yatrik M |
| author_facet | Schwartz, Andrew J Goyert, Joshua W Solanki, Sumeet Kerk, Samuel A Chen, Brandon Castillo, Cristina Hsu, Peggy P Do, Brian T Singhal, Rashi Dame, Michael K Lee, Ho-Joon Spence, Jason R Lakhal-Littleton, Samira Heiden, Matthew G Vander Lyssiotis, Costas A Xue, Xiang Shah, Yatrik M |
| author_sort | Schwartz, Andrew J |
| collection | MIT |
| description | Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours. |
| first_indexed | 2024-09-23T10:41:10Z |
| format | Article |
| id | mit-1721.1/138808 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:41:10Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1388082022-01-05T03:28:31Z Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells Schwartz, Andrew J Goyert, Joshua W Solanki, Sumeet Kerk, Samuel A Chen, Brandon Castillo, Cristina Hsu, Peggy P Do, Brian T Singhal, Rashi Dame, Michael K Lee, Ho-Joon Spence, Jason R Lakhal-Littleton, Samira Heiden, Matthew G Vander Lyssiotis, Costas A Xue, Xiang Shah, Yatrik M Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours. 2022-01-04T19:35:24Z 2022-01-04T19:35:24Z 2021 2022-01-04T19:25:01Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/138808 Schwartz, Andrew J, Goyert, Joshua W, Solanki, Sumeet, Kerk, Samuel A, Chen, Brandon et al. 2021. "Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells." Nature Metabolism, 3 (7). en 10.1038/S42255-021-00406-7 Nature Metabolism Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Schwartz, Andrew J Goyert, Joshua W Solanki, Sumeet Kerk, Samuel A Chen, Brandon Castillo, Cristina Hsu, Peggy P Do, Brian T Singhal, Rashi Dame, Michael K Lee, Ho-Joon Spence, Jason R Lakhal-Littleton, Samira Heiden, Matthew G Vander Lyssiotis, Costas A Xue, Xiang Shah, Yatrik M Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| title | Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| title_full | Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| title_fullStr | Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| title_full_unstemmed | Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| title_short | Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| title_sort | hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells |
| url | https://hdl.handle.net/1721.1/138808 |
| work_keys_str_mv | AT schwartzandrewj hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT goyertjoshuaw hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT solankisumeet hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT kerksamuela hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT chenbrandon hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT castillocristina hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT hsupeggyp hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT dobriant hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT singhalrashi hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT damemichaelk hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT leehojoon hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT spencejasonr hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT lakhallittletonsamira hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT heidenmatthewgvander hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT lyssiotiscostasa hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT xuexiang hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells AT shahyatrikm hepcidinsequestersirontosustainnucleotidemetabolismandmitochondrialfunctionincolorectalcancerepithelialcells |