Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells

被引：298

作者：

Elia, Ilaria ^{[1
,2
,3
]}

Broekaert, Dorien ^{[1
,2
,3
]}

Christen, Stefan ^{[1
,2
,3
]}

Boon, Ruben ^{[4
]}

Radaelli, Enrico ^{[5
,6
]}

Orth, Martin F. ^{[7
]}

Verfaillie, Catherine ^{[4
]}

Gruenewald, Thomas G. P. ^{[7
]}

Fendt, Sarah-Maria ^{[1
,2
,3
]}

机构：

[1] VIB, VIB Ctr Canc Biol, Lab Cellular Metab & Metab Regulat, Herestr 49, B-3000 Leuven, Belgium

[2] Katholieke Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, Herestr 49, B-3000 Leuven, Belgium

[3] Leuven Canc Inst LKI, Herestr 49, B-3000 Leuven, Belgium

[4] Katholieke Univ Leuven, Stem Cell Inst, Herestr 49, B-3000 Leuven, Belgium

[5] Katholieke Univ Leuven, VIB Leuven, Ctr Biol Dis, Herestr 49, B-3000 Leuven, Belgium

[6] Katholieke Univ Leuven, Ctr Human Genet, Herestr 49, B-3000 Leuven, Belgium

[7] Ludwig Maximilians Univ Munchen, Inst Pathol, Max Eder Res Grp Pediat Sarcoma Biol, Thalkirchner Str 36, D-80337 Munich, Germany

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

TUMOR-SUPPRESSOR; BREAST-CANCER; EARLY DISSEMINATION; OXIDASE; GROWTH; RAS; DEHYDROGENASE; BIOSYNTHESIS; EXTRACTION; PHENOTYPE;

D O I：

10.1038/ncomms15267

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Metastases are the leading cause of mortality in patients with cancer. Metastasis formation requires cancer cells to adapt their cellular phenotype. However, how metabolism supports this adaptation of cancer cells is poorly defined. We use 2D versus 3D cultivation to induce a shift in the cellular phenotype of breast cancer cells. We discover that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture. Subsequently, we link proline catabolism to in vivo metastasis formation. In particular, we find that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh is sufficient to impair formation of lung metastases in the orthotopic 4T1 and EMT6.5 mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discover that Prodh is a potential drug target for inhibiting metastasis formation.

引用

页数：11

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