Proteomic Profiling of Extracellular Matrix Components from Patient Metastases Identifies Consistently Elevated Proteins for Developing Nanobodies That Target Primary Tumors and Metastases.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 06 2023
15 06 2023
Historique:
received:
10
05
2022
revised:
08
11
2022
accepted:
19
04
2023
medline:
16
6
2023
pubmed:
26
4
2023
entrez:
26
4
2023
Statut:
ppublish
Résumé
Metastases are hard to detect and treat, and they cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix (ECM) forms a major component of the tumor microenvironment in both primary and metastatic tumors, and certain ECM proteins can be selectively and abundantly expressed in tumors. Nanobodies against ECM proteins that show selective abundance in metastases have the potential to be used as vehicles for delivery of imaging and therapeutic cargoes. Here, we describe a strategy to develop phage-display libraries of nanobodies against ECM proteins expressed in human metastases, using entire ECM-enriched preparations from triple-negative breast cancer (TNBC) and colorectal cancer metastases to different organs as immunogens. In parallel, LC-MS/MS-based proteomics were used to define a metastasis-associated ECM signature shared by metastases from TNBC and colorectal cancer, and this conserved set of ECM proteins was selectively elevated in other tumors. As proof of concept, selective and high-affinity nanobodies were isolated against an example protein from this signature, tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastasis. TNC was abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Immuno-PET/CT showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic nanobodies against tumors and metastases are promising cancer-agnostic tools for delivery of therapeutics to tumor and metastatic ECM. Nanobodies specific for extracellular matrix markers commonly expressed in primary tumors and metastases are promising agents for noninvasive detection of tumors and metastases and potential tools for targeted therapy.
Identifiants
pubmed: 37098922
pii: 726121
doi: 10.1158/0008-5472.CAN-22-1532
pmc: PMC10267678
doi:
Substances chimiques
Single-Domain Antibodies
0
Tenascin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2052-2065Subventions
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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