Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

Batista, Sílvia; Maniati, Eleni; Reynolds, Louise E.; Tavora, Bernardo; Lees, Delphine M.; Fernandez, Isabelle; Elia, George; Casanovas, Oriol; Celso, Cristina Lo; Hagemann, Thorsten; Hodivala‐Dilke, Kairbaan

doi:10.1038/ncomms6054

Cited by 18 publications

(14 citation statements)

References 67 publications

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“…Interestingly, studies performed with myeloid-specific Fak knockout ( Fak KO) mice revealed the ability of FAK to decrease the pathogen-killing capacity of neutrophils (12). In contrast to previous reports, showing decreased metastasis after silencing Fak in tumor cells, or by FAK pharmacologic inhibition (13, 14), hematopoietic Fak deficiency in mice generates a prometastatic microenvironment that enhances tumor metastasis (15). These reports indicate a regulatory role for stromal FAK in cancer growth and spread.…”

Section: Introductioncontrasting

confidence: 90%

Molecular Pathways: Endothelial Cell FAK—A Target for Cancer Treatment

Roy-Luzarraga

Hodivala‐Dilke

2016

Clinical Cancer Research

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The nonreceptor protein tyrosine kinase, focal adhesion kinase (FAK, also known as PTK2), is a key mediator of signal transduction downstream of integrins and growth factor receptors in a variety of cells, including endothelial cells. FAK is upregulated in several advanced-stage solid tumors and has been described to promote tumor progression and metastasis through effects on both tumor cells and stromal cells. This observation has led to the development of several FAK inhibitors, some of which have entered clinical trials (GSK2256098, VS-4718, VS-6062, VS-6063, and BI853520). Resistance to chemotherapy is a serious limitation of cancer treatment and, until recently, most studies were restricted to tumor cells, excluding the possible roles performed by the tumor microenvironment. A recent report identified endothelial cell FAK (EC-FAK) as a major regulator of chemosensitivity. By dysregulating endothelial cell-derived paracrine (also known as angiocrine) signals, loss of FAK solely in the endothelial cell compartment is able to induce chemosensitization to DNA-damaging therapies in the malignant cell compartment and thereby reduce tumor growth. Herein, we summarize the roles of EC-FAK in cancer and development and review the status of FAK-targeting anticancer strategies. Clin Cancer Res; 22(15); 3718-24. Ó2016 AACR.

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Section: Introductioncontrasting

confidence: 90%

Molecular Pathways: Endothelial Cell FAK—A Target for Cancer Treatment

Roy-Luzarraga

Hodivala‐Dilke

2016

Clinical Cancer Research

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“…Invasion and metastasis remain the main obstacles in the effective treatment of breast cancer [16, 17]. Recent evidence indicates that paired-related homeobox protein family play a critical role in tumor progression and drug resistance by promoting cell growth, immune escape and angiogenesis [18].…”

Section: Discussionmentioning

confidence: 99%

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Lv¹,

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Epithelial-mesenchymal transition (EMT) is recognized as a crucial mechanism in breast cancer progression and metastasis. Paired-related homeobox 2 (Prrx2) has been identified as a new EMT inducer in cancer, but the underlying mechanisms are still poorly understood. Methods: The expression of Prrx2 was assessed by immunohistochemistry in breast cancer tissues to evaluate the clinicopathological significance of Prrx2, as well as the correlation between Prrx2 and EMT. Short hairpin RNA knockdown of Prrx2 was used to examine cellular effects of Prrx2, detecte the expression of Wnt/β-catenin signaling and EMT-associated proteins, and observe cell proliferation, invasion and migration abilities in vitro and in vivo. Results: Clinical association studies showed that Prrx2 expression was related to tumor size, lymph node metastasis, tumor node metastasis stages, EMT and poor survival. Results also showed that knockdown of Prrx2 could alter cell morphology, suppressed the abilities of cell proliferation, invasion and migration in breast cancer. Moreover, silencing of Prrx2 induced the mesenchymal-epithelial transition and prevented nuclear translocation of β-catenin, inhibited wnt/β-catenin signaling pathway. Conclusion: Our study indicated that Prrx2 may be an important activator of EMT in human breast cancer and it can serve as a molecular target of therapeutic interventions for breast cancer.

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“…In mice, genetic dissection of the effect of FAK loss in separate compartments of the tumour stroma have indicated that loss of endothelial cell FAK can affect the initiation of tumour angiogenesis and function depending on the temporal regulation of EC-FAK depletion 8,9 . Additionally, heterozygous depletion of FAK can enhance tumour angiogenesis and tumour growth while loss of haematopoetic FAK can enhance cancer metastasis without an apparent effect on primary tumour growth 10 . The impact of these studies lies in elucidating the multiple functions of FAK in different stromal cell types in the control of cancer growth.…”

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confidence: 99%

Cancer associated fibroblast FAK regulates malignant cell metabolism

et al. 2020

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Emerging evidence suggests that cancer cell metabolism can be regulated by cancerassociated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.

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Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

Cited by 18 publications

References 67 publications

Molecular Pathways: Endothelial Cell FAK—A Target for Cancer Treatment

Molecular Pathways: Endothelial Cell FAK—A Target for Cancer Treatment

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Cancer associated fibroblast FAK regulates malignant cell metabolism

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