Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Ghoroghi, Shima; Mary, Benjamin; Larnicol, Annabel; Asokan, Nandini; Klein, Albrecht; Osmani, Naël; Busnelli, Ignacio; Delalande, François; Paul, Nicodéme; Halary, Sébastien; Gros, Frédéric; Fouillen, Laëtitia; Haeberlé, Anne-Marie; Royer, Cathy; Spiegelhalter, Coralie; André-Grégoire, Gwennan; Mittelheisser, Vincent; Detappe, Alexandre; Murphy, Kendelle J.; Timpson, Paul; Carapito, Raphaël; Blot‐Chabaud, Marcel; Gavard, Julie; Vitale, Nicolas; Lefèbvre, Olivier; Goetz, Jacky G.; Hyenne, Vincent

doi:10.7554/elife.61539

Cited by 90 publications

(88 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CRISPR-mediated knockout of RALB significantly increased orthotopic TNBC tumor growth in vivo, increased 3D invasion, and increased cell viability in both adherent and nonadherent culture conditions. Our findings 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 findings.…”

Section: Introductioncontrasting

confidence: 99%

“…Additional studies will be needed determine if these disparate findings are the result of cell line-specific effects or due to differences in study design. It has also been reported [ 20 ] that elevated expression of both RALA and RALB are associated with poor outcome in the TCGA breast cancer patient cohort. Our findings confirm strong association between elevated RALA expression and poor outcome, but do not support a correlation between elevated RALB expression and reduced BC patient survival.…”

Section: Discussionmentioning

confidence: 64%

“…Recently, the C. elegans RAL homolog, RAL-1, was found to be required for the biogenesis and release of extracellular vesicles, important mediators of cell-cell communication [ 36 ]. This group has also shown that shRNA knockdown of either RALA or RALB in 4T1 mammary tumor cells leads to a significant reduction in secreted exosome-like vesicles and reduced lung metastatic capacity [ 20 , 36 ]. Our results suggest that RALA but not RALB contributes to metastatic outgrowth of BC, particularly TNBC, cell lines in the lungs.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Introductioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…For example, KIF20B overexpression in BC correlates with poor prognoses [ 27 ]. Similarly, RALA upregulation is a marker of poor prognosis in BC patients [ 28 ]. Notably, our analysis suggested that proteasome-related pathways may be affected by IFNγ signaling, implying that: 1) some proteasome inhibitors could be tested as pharmacological tools for different cancer types, including BC [ 29 , 30 ]; 2) proteasome subunit (as PSMD8 ) deregulation can result in cancer progression, and resistance to proteasome inhibitors [ 31 , 32 ]; 3) IFNγ increases ISGylation, a protein modification associated with protein stability by competing with the ubiquitination pathway in BC [ [33] , [34] , [35] ]; and 4) the IFNγ repression of proteolysis-associated genes may be helpful in the development of novel strategies to treat this pathology.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes modulated by interferon gamma in breast cancer cells

Tecalco-Cruz

Macı́as-Silva

Ramírez-Jarquín

et al. 2021

Biochemistry and Biophysics Reports

View full text Add to dashboard Cite

Interferon gamma (IFNγ) plays a context-dependent dual tumor-suppressor and pro-tumorigenic roles in cancer. IFNγ induces morphological changes in breast cancer (BC) cells with or without estrogen receptor alpha (ERα) expression. However, IFNγ-regulated genes in BC cells remain unexplored. Here, we performed a cDNA microarray analysis of MCF-7 (ERα+) and MDA-MB-231 (HER2-/PR-/ERα-) cells with and without IFNγ treatment. We identified specific IFNγ−modulated genes in each cell type, and a small group of genes regulated by IFNγ common in both cell types. IFNγ treatment for an extended time mainly repressed gene expression shared by both cell types. Nonetheless, some of these IFNγ-repressed genes were seemingly deregulated in human mammary tumor samples, along with decreased IFNGR1 (an IFNγ receptor) expression. Thus, IFNγ signaling-elicited anti-tumor activities may be mediated by the downregulation of main IFNγ target genes in BC; however, it may be deregulated by the tumor microenvironment in a tumor stage-dependent manner.

show abstract

“…The exocytosis of the ILV-containing MVBs is mainly driven by Rab GTPases at the plasma membrane, specifically RAB27A and RAB27B. Ghoroghi et al identified RalA/B GTPases were a novel molecular mechanism that could control exosome secretion levels via the homeostasis regulation of MVBs 20 . The RalA/B-phospholipase D1 (PLD1)-phosphatidic acid (PA) axis governed exosome biogenesis to a certain extent.…”

Section: Factors Promoting Tumor-derived Exosome Biogenesis Release and Uptake For Bc Metastasismentioning

confidence: 99%

Tumor-derived exosomal components: the multifaceted roles and mechanisms in breast cancer metastasis

Tan

Luo

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

Breast cancer (BC) is the most frequently invasive malignancy and the leading cause of tumor-related mortality among women worldwide. Cancer metastasis is a complex, multistage process, which eventually causes tumor cells to colonize and grow at the metastatic site. Distant organ metastases are the major obstacles to the management of advanced BC patients. Notably, exosomes are defined as specialized membrane-enclosed extracellular vesicles with specific biomarkers, which are found in a wide variety of body fluids. Recent studies have demonstrated that exosomes are essential mediators in shaping the tumor microenvironment and BC metastasis. The transferred tumor-derived exosomes modify the capability of invasive behavior and organ-specific metastasis in recipient cells. BC exosomal components, mainly including noncoding RNAs (ncRNAs), proteins, lipids, are the most investigated components in BC metastasis. In this review, we have emphasized the multifaceted roles and mechanisms of tumor-derived exosomes in BC metastasis based on these important components. The underlying mechanisms mainly include the invasion behavior change, tumor vascularization, the disruption of the vascular barrier, and the colonization of the targeted organ. Understanding the significance of tumor-derived exosomal components in BC metastasis is critical for yielding novel routes of BC intervention.

show abstract

Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Cited by 90 publications

References 77 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

Identification of genes modulated by interferon gamma in breast cancer cells

Tumor-derived exosomal components: the multifaceted roles and mechanisms in breast cancer metastasis

Contact Info

Product

Resources

About