Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis

Fenfen Ji; Pingmei Huang; Qiming Zhou; Lok Hin Ko; Qinyao Wei; Charis Cheuk Lok Chan; Danyu Chen; Huarong Chen; Wei Kang; Alvin Ho Kwan Cheung; Cillian H. Cheng; Jianming Shen; Yasi Pan; Ying Jiao; Lin Zhu; Tat Wai Chik; Peisi Xie; Xiao Liang; Onno Kranenburg; Zongwei Cai; Jun Yu; Chi Chun Wong

doi:10.1016/j.cmet.2026.01.007

Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis

Fenfen Ji
, Pingmei Huang
, Qiming Zhou
, Lok Hin Ko
, Qinyao Wei
, Charis Cheuk Lok Chan
, Danyu Chen
, Huarong Chen
, Wei Kang
, Alvin Ho Kwan Cheung
, Cillian H. Cheng
, Jianming Shen
, Yasi Pan
, Ying Jiao
, Lin Zhu
, Tat Wai Chik
, Peisi Xie
, Xiao Liang
, Onno Kranenburg
, Zongwei Cai^*

Jun Yu^*, Chi Chun Wong^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH₃. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.

Original language	English
Pages (from-to)	794-811.e8
Journal	Cell Metabolism
Volume	38
Issue number	4
Early online date	6 Feb 2026
DOIs	https://doi.org/10.1016/j.cmet.2026.01.007
Publication status	Published - 7 Apr 2026

Keywords

BCAA
BCAT1
BCAT2
branched-chain amino acids
colorectal cancer
dietary restriction
metabolic compartmentalization
metastasis
UMP
uridine monophosphate

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Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axisFinal published version, 18.4 MBLicence: CC BY

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Ji, F., Huang, P., Zhou, Q., Ko, L. H., Wei, Q., Chan, C. C. L., Chen, D., Chen, H., Kang, W., Cheung, A. H. K., Cheng, C. H., Shen, J., Pan, Y., Jiao, Y., Zhu, L., Chik, T. W., Xie, P., Liang, X., Kranenburg, O., ... Wong, C. C. (2026). Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis. Cell Metabolism, 38(4), 794-811.e8. https://doi.org/10.1016/j.cmet.2026.01.007

@article{8a6364d5e52e49c89e91945dc100f30b,

title = "Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis",

abstract = "The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.",

keywords = "BCAA, BCAT1, BCAT2, branched-chain amino acids, colorectal cancer, dietary restriction, metabolic compartmentalization, metastasis, UMP, uridine monophosphate",

author = "Fenfen Ji and Pingmei Huang and Qiming Zhou and Ko, \{Lok Hin\} and Qinyao Wei and Chan, \{Charis Cheuk Lok\} and Danyu Chen and Huarong Chen and Wei Kang and Cheung, \{Alvin Ho Kwan\} and Cheng, \{Cillian H.\} and Jianming Shen and Yasi Pan and Ying Jiao and Lin Zhu and Chik, \{Tat Wai\} and Peisi Xie and Xiao Liang and Onno Kranenburg and Zongwei Cai and Jun Yu and Wong, \{Chi Chun\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s).",

year = "2026",

month = apr,

day = "7",

doi = "10.1016/j.cmet.2026.01.007",

language = "English",

volume = "38",

pages = "794--811.e8",

journal = "Cell Metabolism",

issn = "1550-4131",

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number = "4",

}

Ji, F, Huang, P, Zhou, Q, Ko, LH, Wei, Q, Chan, CCL, Chen, D, Chen, H, Kang, W, Cheung, AHK, Cheng, CH, Shen, J, Pan, Y, Jiao, Y, Zhu, L, Chik, TW, Xie, P, Liang, X, Kranenburg, O, Cai, Z, Yu, J & Wong, CC 2026, 'Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis', Cell Metabolism, vol. 38, no. 4, pp. 794-811.e8. https://doi.org/10.1016/j.cmet.2026.01.007

TY - JOUR

T1 - Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis

AU - Ji, Fenfen

AU - Huang, Pingmei

AU - Zhou, Qiming

AU - Ko, Lok Hin

AU - Wei, Qinyao

AU - Chan, Charis Cheuk Lok

AU - Chen, Danyu

AU - Chen, Huarong

AU - Kang, Wei

AU - Cheung, Alvin Ho Kwan

AU - Cheng, Cillian H.

AU - Shen, Jianming

AU - Pan, Yasi

AU - Jiao, Ying

AU - Zhu, Lin

AU - Chik, Tat Wai

AU - Xie, Peisi

AU - Liang, Xiao

AU - Kranenburg, Onno

AU - Cai, Zongwei

AU - Yu, Jun

AU - Wong, Chi Chun

PY - 2026/4/7

Y1 - 2026/4/7

N2 - The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.

AB - The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.

KW - BCAA

KW - BCAT1

KW - BCAT2

KW - branched-chain amino acids

KW - colorectal cancer

KW - dietary restriction

KW - metabolic compartmentalization

KW - metastasis

KW - UMP

KW - uridine monophosphate

UR - https://www.scopus.com/pages/publications/105033015115

U2 - 10.1016/j.cmet.2026.01.007

DO - 10.1016/j.cmet.2026.01.007

M3 - Article

C2 - 41653924

AN - SCOPUS:105033015115

SN - 1550-4131

VL - 38

SP - 794-811.e8

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis

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