Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

Ren, Ding; Zhu, Xiaoping; Kong, Ren; Zhao, Zhenze; Sheng, Jianting; Wang, Jiang; Xu, Xiaoyun; Liu, Jiyong; Cui, Kemi; Zhang, Xiang H.-F.; Zhao, Hong; Wong, Stephen T.C.

doi:10.1158/0008-5472.can-17-2994

Cited by 59 publications

(63 citation statements)

References 50 publications

(66 reference statements)

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“…Among others, the tumor microenvironment is composed of cancer stem cells (CSCs), partially differentiated progenitor cells, and fully differentiated end-stage cells [6]. Recent findings attribute to CSCs the primary responsibility for enhanced malignancy since they can complete the two stages of metastases formation ( Figure 1) [7]. However, during cancer progression, other cells undergo an epithelialmesenchymal transition (EMT), changing their plasticity by morphological and phenotypical conversions [8,9].…”

Section: Bm Pathophysiologymentioning

confidence: 99%

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

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Section: Bm Pathophysiologymentioning

confidence: 99%

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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“…PCDH7 was recently shown to promote metastasis of lung and breast cancer cells (10,39), further supporting the importance of this protein in multiple aspects of tumor biology. Consistent with these observations, our studies revealed that Pcdh7 depletion in KP mice reduced tumor invasiveness in vivo.…”

Section: Pcdh7 Is An Actionable Therapeutic Target In Lung Adenocarcimentioning

confidence: 83%

Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function

Zhou

Padanad

Evers

et al. 2019

Molecular Cancer Research

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PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. Although PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest contextdependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesis in vivo is needed to evaluate the therapeutic potential of its inhibition. Here, we report the analysis of novel PCDH7 gain-and loss-of-function mouse models and provide compelling evidence that this cell-surface protein acts as a potent lung cancer driver. Employing a Creinducible transgenic allele, we demonstrated that enforced PCDH7 expression significantly accelerates Kras G12D -driven lung tumorigenesis and potentiates MAPK pathway activa-tion. Furthermore, we performed in vivo somatic genome editing with CRISPR/Cas9 in Kras LSL-G12D ; Tp53 fl/fl (KP) mice to assess the consequences of PCDH7 loss of function. Inactivation of PCDH7 in KP mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-activation of ERK1/2. Together, these findings establish a critical oncogenic function for PCDH7 in vivo and highlight the therapeutic potential of PCDH7 inhibition for lung cancer. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the new inducible transgenic model described here provides a robust experimental system for broadly elucidating the effects of PCDH7 overexpression in vivo. Implications:In this study, we establish a critical oncogenic function for PCDH7 in vivo using novel mouse models and CRISPR/Cas9 genome editing, and we validate the therapeutic potential of PCDH7 inhibition for lung cancer.Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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“…PCDH7 was recently shown to promote metastasis of lung and breast cancer cells (10,34), further supporting the importance of this protein in multiple aspects of tumor biology. Consistent with these observations, our studies revealed that Pcdh7 depletion in KP mice reduced tumor invasiveness in vivo.…”

Section: Pcdh7 Is An Actionable Therapeutic Target In Lung Adenocarcimentioning

confidence: 83%

Modulation of mutantKras^G12D-driven lung tumorigenesisin vivoby gain or loss of PCDH7 function

Zhou

Evers

Padanad

et al. 2018

Preprint

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PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. While PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesis in vivo is needed to evaluate the therapeutic potential of its inhibition. Here we report the analysis of novel PCDH7 gain-and loss-of-function mouse models and provide compelling evidence that this cell-surface protein acts as a potent lung cancer driver. Employing a Cre-inducible transgenic allele, we demonstrated that enforced PCDH7 expression significantly accelerates Kras G12D -driven lung tumorigenesis and potentiates MAPK pathway activation. Furthermore, we performed in vivo somatic genome editing with CRISPR/Cas9 in Kras LSL-G12D ; Tp53 fl/fl (KP) mice to assess the consequences of PCDH7 loss of function. Inactivation of PCDH7 in KP mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-activation of ERK1/2. Together, these findings establish a critical oncogenic function for PCDH7 in vivo and highlight the therapeutic potential of PCDH7 inhibition for lung cancer. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the new inducible transgenic model described here provides a robust experimental system for broadly elucidating the effects of PCDH7 overexpression in vivo.

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Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

Cited by 59 publications

References 50 publications

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function

Modulation of mutantKras^G12D-driven lung tumorigenesisin vivoby gain or loss of PCDH7 function

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Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

Cited by 59 publications

References 50 publications

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function

Modulation of mutantKrasG12D-driven lung tumorigenesisin vivoby gain or loss of PCDH7 function

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Modulation of mutantKras^G12D-driven lung tumorigenesisin vivoby gain or loss of PCDH7 function