Downregulating Neuropilin-2 Triggers a Novel Mechanism Enabling EGFR-Dependent Resistance to Oncogene-Targeted Therapies

Rizzolio, Sabrina; Battistini, Chiara; Cagnoni, Gabriella; Apicella, Maria; Vella, Viviana; Giordano, Silvia; Tamagnone, Luca

doi:10.1158/0008-5472.can-17-2020

Cited by 24 publications

(19 citation statements)

References 32 publications

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“…Pathway enrichment analyses showed that NRP-2 mediates tumor progression through multiple oncogenic signaling pathways including EGFR, CCKR, angiogenesis and various growth factors (VEGF, FGF, PDGF) signaling axes. EGFR signaling enrichment upon NRP-2 expression contrasts with a report showing that the acquisition of resistance to therapy in MET-addicted cancer cells is dependent on NRP-2 downregulation [47]. This question was not addressed in our study since MET levels are almost undetectable in our models.…”

Section: Discussioncontrasting

confidence: 76%

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Bollard

Patte

Radkova

et al. 2019

The Journal of Pathology

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The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI‐NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI‐NETs. Interestingly the expression of its receptor neuropilin‐2 (NRP‐2) was still maintained. This study aimed at deciphering the potential role of NRP‐2 as a contributor to SI‐NET progression. The role of NRP‐2 in SI‐NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI‐NET tissues showed that membranous NRP‐2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP‐2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP‐2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP‐2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP‐2 as a potential therapeutic target for SI‐NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussioncontrasting

confidence: 76%

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Bollard

Patte

Radkova

et al. 2019

The Journal of Pathology

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“…Neuropilin 2 overexpression decreases EGFR expression and resistance to MET-targeted therapies (Rizzolio et al, 2018a).…”

Section: Resistance To Targeted Therapiesmentioning

confidence: 99%

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

Dumond

Pagès

2020

Front. Cell Dev. Biol.

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Angiogenesis is one of the key mechanisms involved in tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors (VEGFR) represent one of the major signaling pathways which mediates angiogenesis. The VEGF/VEGFR axis was intensively targeted by monoclonal antibodies or by tyrosine kinase inhibitors to destroy the tumor vascular network. By inhibiting oxygen and nutrient supply, this strategy was supposed to cure cancers. However, despite a lengthening of the progression free survival in several types of tumors including colon, lung, breast, kidney, and ovarian cancers, modest improvements in overall survival were reported. Anti-angiogenic therapies targeting VEGF/VEGFR are still used in colon and ovarian cancer and remain reference treatments for renal cell carcinoma. Although the concept of inhibiting angiogenesis remains relevant, new targets need to be discovered to improve the therapeutic index of anti-VEGF/VEGFR. Neuropilin 1 and 2 (NRP1/2), initially described as neuronal receptors, stimulate angiogenesis, lymphangiogenesis and immune tolerance. Moreover, overexpression of NRPs in several tumors is synonymous of patients' shorter survival. This article aims to overview the different roles of NRPs in cells constituting the tumor microenvironment to highlight the therapeutic relevance of their targeting.

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“…SEMA3s and their receptors have been reported to be related with drug responses in a number of cancer types [3,[59][60][61]. We next investigated the expression of NRPs and PLXNs in NCI-60 cell lines and systematically tested the correlation between their expression levels with drug sensitivity score of over 200 chemotherapy drugs.…”

Section: Neuropilins and Plexins Are Associated With Tumor Stemness Amentioning

confidence: 99%

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

Zhang

Shao

2020

Cancers

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Class-3 semaphorins (SEMA3s), initially characterized as axon guidance cues, have been recognized as key regulators for immune responses, angiogenesis, tumorigenesis and drug responses. The functions of SEMA3s are attributed to the activation of downstream signaling cascades mainly mediated by cell surface receptors neuropilins (NRPs) and plexins (PLXNs), yet their roles in human cancers are not completely understood. Here, we provided a detailed pan-cancer analysis of NRPs and PLXNs in their expression, and association with key signal transducers, patient survival, tumor microenvironment (TME), and drug responses. The expression of NRPs and PLXNs were dysregulated in many cancer types, and the majority of them were further dysregulated in metastatic tumors, indicating a role in metastatic progression. Importantly, the expression of these genes was frequently associated with key transducers, patient survival, TME, and drug responses; however, the direction of the association varied for the particular gene queried and the specific cancer type/subtype tested. Specifically, NRP1, NRP2, PLXNA1, PLXNA3, PLXNB3, PLXNC1, and PLXND1 were primarily associated with aggressive phenotypes, whereas the rest were more associated with favorable prognosis. These data highlighted the need to study each as a separate entity in a cancer type- and subtype-dependent manner.

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Downregulating Neuropilin-2 Triggers a Novel Mechanism Enabling EGFR-Dependent Resistance to Oncogene-Targeted Therapies

Cited by 24 publications

References 32 publications

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

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