Identification of Caveolin-1 as a Potential Causative Factor in the Generation of Trastuzumab Resistance in Breast Cancer Cells

Sekhar, Sreeja; Kasai, Tomonari; Satoh, Ayano; Shigehiro, Tsukasa; Mizutani, Akifumi; Murakami, Hiroshi; El‐Aarag, Bishoy; Salomon, David; Massaguer, Anna; Llorens, Rafael de; Seno, Masaharu

doi:10.7150/jca.6470

Cited by 35 publications

(39 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cav1 protein levels corresponded with these results in cell lines and in clinical samples, showing a correlation between Cav1, Lef1, and Vim expression. Similarly, Cav1 expression has been found in drug-resistant cells in lung, colon, and HER2-positive breast cancer (50,51). However, under experimental Lef1 o/e in MCF7, although CAV1 mRNA increased, we did not observe increased Cav1 protein expression.…”

Section: Discussionsupporting

confidence: 51%

Single-Cell Analysis Reveals a Preexisting Drug-Resistant Subpopulation in the Luminal Breast Cancer Subtype

et al. 2019

View full text Add to dashboard Cite

Drug resistance is a major obstacle in the treatment of breast cancer. Surviving cells lead to tumor recurrence and metastasis, which remains the main cause of cancer-related mortality. Breast cancer is also highly heterogeneous, which hinders the identification of individual cells with the capacity to survive anticancer treatment. To address this, we performed extensive single-cell gene-expression profiling of the luminal-type breast cancer cell line MCF7 and its derivatives, including docetaxel-resistant cells. Upregulation of epithelial-to-mesenchymal transition and stemness-related genes and downregulation of cell-cycle-related genes, which were mainly regulated by LEF1, were observed in the drug-resistant cells. Interestingly, a small number of cells in the parental population exhibited a gene-expression profile similar to that of the drug-resistant cells, indicating that the untreated parental cells already contained a rare subpopulation of stem-like cells with an inherent predisposition toward docetaxel resistance. Our data suggest that during chemotherapy, this population may be positively selected, leading to treatment failure. Significance: This study highlights the role of breast cancer intratumor heterogeneity in drug resistance at a single-cell level.

show abstract

Section: Discussionsupporting

confidence: 51%

Single-Cell Analysis Reveals a Preexisting Drug-Resistant Subpopulation in the Luminal Breast Cancer Subtype

et al. 2019

View full text Add to dashboard Cite

show abstract

“…5A). Since it has been reported that Her2 can be taken up via caveolin-1 dependent endocytosis and, to a lesser extent, clathrin-mediated endocytosis, [59][60][61][62] this difference likely represents anti-Her2-scFv-exosomes binding to Her2 and concomitant internalisation with the receptor. Thus, by directing exosomes to bind to a specific cell surface receptor, we have shown that it is possible to alter the trafficking and likely intracellular fate of the cargo.…”

Section: Discussionmentioning

confidence: 99%

High affinity single-chain variable fragments are specific and versatile targeting motifs for extracellular vesicles

Longatti¹,

Schindler²,

Collinson³

et al. 2018

Nanoscale

View full text Add to dashboard Cite

Exosomes are extracellular vesicles that mediate cell-to-cell communication by transferring biological cargo, such as DNA, RNA and proteins. Through genetic engineering of exosome-producing cells or manipulation of purified exosomes, it is possible to load exosomes with therapeutic molecules and target them to specific cells via the display of targeting moieties on their surface. This provides an opportunity to exploit a naturally-occurring biological process for therapeutic purposes. In this study, we explored the potential of single chain variable fragments (scFv) as targeting domains to achieve delivery of exosomes to cells expressing a cognate antigen. We generated exosomes targeting the Her2 receptor and, by varying the affinity of the scFvs and the Her2 expression level on recipient cells, we determined that both a high-affinity anti-Her2-scFv (K≤ 1 nM) and cells expressing a high level (≥10 copies per cell) of Her2 were optimally required to enable selective uptake. We also demonstrate that targeting exosomes to cells via a specific cell surface receptor can alter their intracellular trafficking route, providing opportunities to influence the efficiency of delivery and fate of intracellular cargo. These experiments provide solid data to support the wider application of exosomes displaying antibody fragments as vehicles for the targeted delivery of therapeutic molecules.

show abstract

“…Clathrin dependent and independent mechanisms have been implicated in the endocytosis of HER2 and Tz (8,31,32) and in crosslinking-based approaches for enhanced receptor internalisation (21). To investigate the contribution of specific pathways to crosslinking induced Tz:HER2 endocytosis we used siRNA to deplete critical endocytic targets (33).…”

Section: Tz:her2 Crosslinking Induced Endocytosis Occurs By Clathrin mentioning

confidence: 99%

Strategic Trastuzumab Mediated Crosslinking Driving Concomitant HER2 and HER3 Endocytosis and Degradation in Breast Cancer

Wymant¹,

Sayers²,

Muir³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Efficacious anticancer therapies for targeting plasma membrane receptors with antibody based therapeutics are often contingent on sufficient endocytic delivery of receptor and conjugate to lysosomes. This results in downregulation of receptor activity and, in the case of antibody-drug conjugates (ADCs), intracellular release of a drug payload. The oncogenic receptor HER2 is a priority therapeutic target in breast cancer. Known as an "endocytosis resistant" receptor, HER2 thwarts the receptor downregulating efficiency of the frontline treatment trastuzumab and reduces the potential of trastuzumab-based therapies such as trastuzumab-emtansine. We previously demonstrated that strategically inducing trastuzumab and HER2 crosslinking in breast cancer cells promoted endocytosis and lysosomal delivery of the HER2-trastuzumab complex, stimulating downregulation of the receptor. Here we reveal that HER3, but not EGFR, is also concomitantly downregulated with HER2 after crosslinking. This is accompanied by strong activation of MEK/ERK pathway that we show does not directly contribute to HER2/trastuzumab endocytosis. We show that crosslinking induced trastuzumab endocytosis occurs via clathrin-dependent and independent pathways and is an actin-dependent process. Detailed ultrastructural studies of the plasma membrane highlight crosslinking-specific remodelling of microvilli and induction of extensive ruffling. Investigations in a cell model of acquired trastuzumab resistance demonstrate, for the first time, that they are refractory to crosslinking induced HER2 endocytosis and downregulation. This implicates further arrest of HER2 internalisation in developing trastuzumab resistance. Overall our findings highlight the potential of receptor crosslinking as a therapeutic strategy for cancer while exposing the ability of cancer cells to develop resistance via endocytic mechanisms.

show abstract

Identification of Caveolin-1 as a Potential Causative Factor in the Generation of Trastuzumab Resistance in Breast Cancer Cells

Cited by 35 publications

References 51 publications

Single-Cell Analysis Reveals a Preexisting Drug-Resistant Subpopulation in the Luminal Breast Cancer Subtype

Single-Cell Analysis Reveals a Preexisting Drug-Resistant Subpopulation in the Luminal Breast Cancer Subtype

High affinity single-chain variable fragments are specific and versatile targeting motifs for extracellular vesicles

Strategic Trastuzumab Mediated Crosslinking Driving Concomitant HER2 and HER3 Endocytosis and Degradation in Breast Cancer

Contact Info

Product

Resources

About