Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer

Wang, Mengyuan; Huang, Man; Wang, Chaoyi; Tang, Xiaoying; Wang, Jian-Gen; Yang, Yongde; Xiong, Xin; Gao, Chaowei

doi:10.3389/fonc.2021.682021

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…sEVs are important players in intercellular communication and are implicated in tumorigenesis and metastasis [ 8 – 11 , 13 , 14 , 16 ]. On the other hand, lactadherin overexpression has been associated with poor prognosis in several types of cancers, including BC [ 60 – 62 ]⁠. Thus, we evaluated the presence of this protein in BC cell-secreted sEVs obtained from MCF7, T47D, and MDA-MB-231 BC cell supernatants using ultracentrifugation (sEV-MCF7, sEV-T47D, and sEV-MDA231).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities

Durán-Jara,

del Campo,

Gutiérrez

et al. 2024

Biol Res

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Background Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted glycoprotein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis. Results We show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV-MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231. Conclusions As to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites and metastatic tumor nodules. These results increase our understanding on the role of lactadherin in sEVs as promoter of metastatic capacities which can be used as a therapeutic option for BC and other malignancies.

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Section: Resultsmentioning

confidence: 99%

“…It has been shown that lactadherin is associated with poor prognosis and bad outcomes in several types of cancer [ 43 , 60 – 62 ]. However, little is known about the role and importance of its presence in sEVs, and whether it can influence sEV-mediated tumorigenic and/or pro-metastatic effects.…”

Section: Discussionmentioning

confidence: 99%

Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities

Durán-Jara,

del Campo,

Gutiérrez

et al. 2024

Biol Res

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“…Hapln3/LP3 is widely expressed, mainly outside the brain (Spicer et al, 2003). It was reported to be involved in breast, kidney and prostate cancer (Strand et al, 2014;Wang et al, 2021;Ding et al, 2023) but its role in brain ischemia has not yet been investigated.…”

Section: Ecm Molecules In Perineuronal Netsmentioning

confidence: 99%

A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke

Chmelova,

Androvic,

Kirdajova

et al. 2023

Front. Cell. Neurosci.

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IntroductionModification of the extracellular matrix (ECM) is one of the major processes in the pathology of brain damage following an ischemic stroke. However, our understanding of how age-related ECM alterations may affect stroke pathophysiology and its outcome is still very limited.MethodsWe conducted an ECM-targeted re-analysis of our previously obtained RNA-Seq dataset of aging, ischemic stroke and their interactions in young adult (3-month-old) and aged (18-month-old) mice. The permanent middle cerebral artery occlusion (pMCAo) in rodents was used as a model of ischemic stroke. Altogether 56 genes of interest were chosen for this study.ResultsWe identified an increased activation of the genes encoding proteins related to ECM degradation, such as matrix metalloproteinases (MMPs), proteases of a disintegrin and metalloproteinase with the thrombospondin motifs (ADAMTS) family and molecules that regulate their activity, tissue inhibitors of metalloproteinases (TIMPs). Moreover, significant upregulation was also detected in the mRNA of other ECM molecules, such as proteoglycans, syndecans and link proteins. Notably, we identified 8 genes where this upregulation was enhanced in aged mice in comparison with the young ones. Ischemia evoked a significant downregulation in only 6 of our genes of interest, including those encoding proteins associated with the protective function of ECM molecules (e.g., brevican, Hapln4, Sparcl1); downregulation in brevican was more prominent in aged mice. The study was expanded by proteome analysis, where we observed an ischemia-induced overexpression in three proteins, which are associated with neuroinflammation (fibronectin and vitronectin) and neurodegeneration (link protein Hapln2). In fibronectin and Hapln2, this overexpression was more pronounced in aged post-ischemic animals.ConclusionBased on these results, we can conclude that the ratio between the protecting and degrading mechanisms in the aged brain is shifted toward degradation and contributes to the aged tissues’ increased sensitivity to ischemic insults. Altogether, our data provide fresh perspectives on the processes underlying ischemic injury in the aging brain and serve as a freely accessible resource for upcoming research.

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“…This gene fusion was much more frequent in TNBC than in other subtypes. The authors further validated the presence of the MFGE8–HPLN3 gene fusion in TNBC biopsies, and predicted the length of the encoded protein, suggesting its critical role in TNBC biology, and a possible clinical application as a new biomarker [ 47 ]. In Table 1 , we listed the main discoveries of lactadherin research regarding cancer development and its importance as a biomarker of this disease.…”

Section: Lactadherin As a Biomarker Of Tumor Subtype Progression And ...mentioning

confidence: 99%

Lactadherin: From a Well-Known Breast Tumor Marker to a Possible Player in Extracellular Vesicle-Mediated Cancer Progression

Durán-Jara

Vera-Tobar

Lobos-González

2022

IJMS

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Lactadherin is a secreted glycoprotein associated with the milk fat globule membrane, which is highly present in the blood and in the mammary tissue of lactating women. Several biological functions have been associated with this protein, mainly attributable to its immunomodulatory role promoting phagocyte-mediated clearance of apoptotic cells. It has been shown that lactadherin also plays important roles in cell adhesion, the promotion of angiogenesis, and tissue regeneration. On the other hand, this protein has been used as a marker of breast cancer and tumor progression. Recently, high levels of lactadherin has been associated with poor prognosis and decreased survival, not only in breast cancer, but also in melanoma, ovarian, colorectal, and other types of cancer. Although the mechanisms responsible for the tumor-promoting effects attributed to lactadherin have not been fully elucidated, a growing body of literature indicates that lactadherin could be a promising therapeutic target and/or biomarker for breast and other tumors. Moreover, recent studies have shown its presence in extracellular vesicles derived from cancer cell lines and cancer patients, which was associated with cancer aggressiveness and worse prognosis. Thus, this review will focus on the link between lactadherin and cancer development and progression, its possible use as a cancer biomarker and/or therapeutic target, concluding with a possible role of this protein in cellular communication mediated by extracellular vesicles

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Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer

Cited by 6 publications

References 43 publications

Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities

Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities

A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke

Lactadherin: From a Well-Known Breast Tumor Marker to a Possible Player in Extracellular Vesicle-Mediated Cancer Progression

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