RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Nászai, Máté; Bellec, Karen; Yu, Yiqiang; Román-Fernández, Álvaro; Sandilands, Emma; Johansson, Joel; Campbell, Andrew D.; Norman, Jim; Sansom, Owen J.; Bryant, David M.; Cordero, Julia B.

doi:10.1101/2020.10.07.329607

Cited by 3 publications

(2 citation statements)

References 113 publications

(124 reference statements)

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“…Our ndings are dissimilar from those reported in three recent studies where RALA and RALB were found to play similar roles in BC cell line models [20,21] or transient silencing of RALB was found to decrease BC cell line invasion [22]. In silico analyses utilizing the large TCGA and METABRIC breast cancer patient gene expression databases uncovered paradoxical associations between survival and RALA and RALB expression in support of our in vitro and in vivo ndings.…”

Section: Introductioncontrasting

confidence: 99%

The Small G-Protein RalA Promotes Progression and Metastasis of Triple Negative Breast Cancer

Thies

Cole

Schafer

et al. 2021

Preprint

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Background: Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC. Methods: The necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models. Results: Knockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo. Conclusions: Together, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC.

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Section: Introductioncontrasting

confidence: 99%

The Small G-Protein RalA Promotes Progression and Metastasis of Triple Negative Breast Cancer

Thies

Cole

Schafer

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Upon tissue damage, internalization of the BMP receptor, Tkv, in ISCs requires Awd, a facilitator of dynamin endocytic function; this promotes Mad activation driving ISC return to quiescence [33]. Similarly, endocytosis of the Wnt receptor (Fz3) and EGFR is regulated by the RalA GTPase, which is essential for the regenerative response of ISCs after damage [34,35].…”

Section: Cell-autonomous Regulation Of Proliferationmentioning

confidence: 99%

An amuse-bouche of stem cell regulation: Underlying principles and mechanisms from adult Drosophila intestinal stem cells

Boumard

Bardin

2021

Current Opinion in Cell Biology

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The small G-protein RalA promotes progression and metastasis of triple-negative breast cancer

et al. 2021

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Background Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC. Methods The necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models. Results Knockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo. Conclusions Together, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC.

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RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Cited by 3 publications

References 113 publications

The Small G-Protein RalA Promotes Progression and Metastasis of Triple Negative Breast Cancer

The Small G-Protein RalA Promotes Progression and Metastasis of Triple Negative Breast Cancer

An amuse-bouche of stem cell regulation: Underlying principles and mechanisms from adult Drosophila intestinal stem cells

The small G-protein RalA promotes progression and metastasis of triple-negative breast cancer

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