MassIVE MSV000089136

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Exploiting ECM signatures associated with human metastases for targeting tumors and metastases using alpaca-derived nanobodies

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Description

Jailkhani N, Clauser KR, Mak H, Rickelt S, Tian C, Whittaker CA, Tanabe KK, Purdy SR, Carr SA, and Hynes RO.2022. Metastases are hard to detect and treat, and cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix or 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 such tumors. We propose that nanobodies against ECM proteins that show selective abundance in metastases can be used as vehicles for delivery of imaging and therapeutic cargoes. To gain a deeper understanding of the microenvironment of human metastases, we describe here an LC-MS/MS-based ECM signature shared by human TNBC and CRC metastases to different organs and provide evidence that this conserved set of ECM proteins is selectively elevated in other tumors. We also describe phage-display libraries of nanobodies raised against ECM-enriched preparations from human metastases from TNBC and CRC. As proof of concept, we developed selective and specific, high-affinity nanobodies against an example signature protein, Tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastases. We report that TNC is abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Using immuno-PET/CT we showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic anti-tumor nanobodies are promising cancer-agnostic, in vivo tools for the delivery of therapeutics to tumor and metastatic ECM. [doi:10.25345/C5VH5CN5T] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: extracellular matrix

Contact

Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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