Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado, Maria del Mar; Medina, Julia I.; Velázquez, Luis; Dharmawardhane, Suranganie

doi:10.3389/fcell.2020.00201

Cited by 71 publications

(67 citation statements)

References 235 publications

(266 reference statements)

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“…2B ). Interestingly, despite the similarities in signalling pathways between RAC1 and CDC42 and being close homologues 4 , 5 , 44 , CDC42 expression is unaffected by loss of RAC1 (Supplementary Fig. 2C ).…”

Section: Resultsmentioning

confidence: 99%

A RAC-GEF network critical for early intestinal tumourigenesis

et al. 2021

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RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2−/−Vav3−/−Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

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Section: Resultsmentioning

confidence: 99%

A RAC-GEF network critical for early intestinal tumourigenesis

et al. 2021

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“…Although prior work in melanoma established NME1 as a metastasis suppressor gene, [43][44][45] we recently reported its upregulation in lung metastases that display increased OXPHOS. Given that the main function of NME1 is to transfer phosphate from ATP to produce GTP, we hypothesized that NME1 may use ATP generated through OXPHOS to create GTP for G protein signaling pathways that promote metastasis 37,38 . Using our culture-transplant system, we found that NME1 overexpression results in a 4-fold increase in spontaneous lung metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Several G proteins such as RAC1 an CDC42 promote cell migration and growth and have established pro-metastatic functions 38 . We hypothesized that OXPHOS promotes metastasis in PDX cells through NME1, and tested whether NME1 overexpression promotes metastasis using our culture-transplant system.…”

Section: Nme1 Promotes Lung Metastasis From Patient Tumor Cellsmentioning

confidence: 99%

Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis

Ma¹,

Hernandez²,

Lefebvre³

et al. 2020

Preprint

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Metastatic disease carries a poor prognosis and its study is limited by the availability of authentic experimental models. Here, we present a 3D tumor sphere culture-transplant system that facilitates expansion and modulation of patient-derived xenograft (PDX) cells for use in functional experimental metastasis assays. RNA sequencing shows PDX tumor spheres maintain fundamental properties of native tumor cells. In vivo transplantation studies demonstrate cultured cells yield robust spontaneous and experimental metastasis following orthotopic and intravenous or intracardiac delivery, respectively. Pharmacologic inhibition of previously reported metastasis-promoting pathways also inhibits metastasis of PDX cells after culture, validating our approach. Finally, we used our culture-transplant system to demonstrate a new role of the metabolic enzyme NME1 in promoting breast cancer metastasis. Thus, we present a novel method for authentic propagation, engineering and transplantation of PDX models for functional studies of metastasis using bona fide patient tumor cells.

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“…This includes their ability to inhibit cell proliferation and migration in a variety of prostate cancer cell lines including PC-3 ( PTEN −/− ) and DU145 ( PTEN +/− ) cells in vitro, and ZCL367 is also reported to significantly inhibit tumor growth in a xenograft model of lung cancer [ 292 ]. Intriguingly, both RAC1 activity and CDC42 activity have been associated with therapeutic resistance in different cancer types, including enzalutamide resistance in CRPC, and RAC/CDC42 inhibition has been suggested as a potential approach to overcome resistance to PI3K–AKT–mTOR-targeted treatments [ 294 , 295 , 296 , 297 , 298 ]. Although RAC/CDC42-specific inhibitors remain to be explored clinically, one FDA-approved non-steroidal anti-inflammatory drug (NSAID), R-ketorolac, has been shown to potently inhibit RAC1 and CDC42, and has been demonstrated to improve ovarian cancer patient survival (NCT02470299), suggesting that GTPase targeting could be efficacious in other human cancers with elevated expression and activity of RAC1 and/or CDC42 [ 299 ].…”

Section: Targeting Pten-deficient Prostate Cancermentioning

confidence: 99%

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Turnham

Bullock

Dass

et al. 2020

Cells

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Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

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Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Cited by 71 publications

References 235 publications

A RAC-GEF network critical for early intestinal tumourigenesis

A RAC-GEF network critical for early intestinal tumourigenesis

Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

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