Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer

Brock A. Humphries, Johanna M. Buschhaus, Yu Chih Chen, Henry R. Haley, Tonela Qyli, Benjamin Chiang, Nathan Shen, Shrila Rajendran, Alyssa Cutter, Yu Heng Cheng, Yu Ting Chen, Jason Cong, Phillip C. Spinosa, Euisik Yoon, Kathryn E. Luker, Gary D. Luker

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. Implications: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.

Original languageEnglish
Pages (from-to)1142-1154
Number of pages13
JournalMolecular Cancer Research
Volume17
Issue number5
DOIs
Publication statusPublished - 2019 May

Fingerprint

Triple Negative Breast Neoplasms
Plasminogen Activator Inhibitor 1
Actin Cytoskeleton
Neoplasms
Xenograft Model Antitumor Assays
Actins
Breast Neoplasms
Neoplasm Metastasis
Stress Fibers
Optical Imaging
Glycolysis
Coculture Techniques
Fibrin
Heterografts
NAD
Cell Movement
Extracellular Matrix
Microscopy

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Humphries, Brock A. ; Buschhaus, Johanna M. ; Chen, Yu Chih ; Haley, Henry R. ; Qyli, Tonela ; Chiang, Benjamin ; Shen, Nathan ; Rajendran, Shrila ; Cutter, Alyssa ; Cheng, Yu Heng ; Chen, Yu Ting ; Cong, Jason ; Spinosa, Phillip C. ; Yoon, Euisik ; Luker, Kathryn E. ; Luker, Gary D. / Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 5. pp. 1142-1154.
@article{029512e07bdb49fb95bf43aae59b59d0,
title = "Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer",
abstract = "Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. Implications: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.",
author = "Humphries, {Brock A.} and Buschhaus, {Johanna M.} and Chen, {Yu Chih} and Haley, {Henry R.} and Tonela Qyli and Benjamin Chiang and Nathan Shen and Shrila Rajendran and Alyssa Cutter and Cheng, {Yu Heng} and Chen, {Yu Ting} and Jason Cong and Spinosa, {Phillip C.} and Euisik Yoon and Luker, {Kathryn E.} and Luker, {Gary D.}",
year = "2019",
month = "5",
doi = "10.1158/1541-7786.MCR-18-0836",
language = "English",
volume = "17",
pages = "1142--1154",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

Humphries, BA, Buschhaus, JM, Chen, YC, Haley, HR, Qyli, T, Chiang, B, Shen, N, Rajendran, S, Cutter, A, Cheng, YH, Chen, YT, Cong, J, Spinosa, PC, Yoon, E, Luker, KE & Luker, GD 2019, 'Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer', Molecular Cancer Research, vol. 17, no. 5, pp. 1142-1154. https://doi.org/10.1158/1541-7786.MCR-18-0836

Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer. / Humphries, Brock A.; Buschhaus, Johanna M.; Chen, Yu Chih; Haley, Henry R.; Qyli, Tonela; Chiang, Benjamin; Shen, Nathan; Rajendran, Shrila; Cutter, Alyssa; Cheng, Yu Heng; Chen, Yu Ting; Cong, Jason; Spinosa, Phillip C.; Yoon, Euisik; Luker, Kathryn E.; Luker, Gary D.

In: Molecular Cancer Research, Vol. 17, No. 5, 05.2019, p. 1142-1154.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer

AU - Humphries, Brock A.

AU - Buschhaus, Johanna M.

AU - Chen, Yu Chih

AU - Haley, Henry R.

AU - Qyli, Tonela

AU - Chiang, Benjamin

AU - Shen, Nathan

AU - Rajendran, Shrila

AU - Cutter, Alyssa

AU - Cheng, Yu Heng

AU - Chen, Yu Ting

AU - Cong, Jason

AU - Spinosa, Phillip C.

AU - Yoon, Euisik

AU - Luker, Kathryn E.

AU - Luker, Gary D.

PY - 2019/5

Y1 - 2019/5

N2 - Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. Implications: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.

AB - Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. Implications: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.

UR - http://www.scopus.com/inward/record.url?scp=85066131063&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066131063&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-18-0836

DO - 10.1158/1541-7786.MCR-18-0836

M3 - Article

AN - SCOPUS:85066131063

VL - 17

SP - 1142

EP - 1154

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 5

ER -