PMID- 37098922
OWN - NLM
STAT- MEDLINE
DCOM- 20230616
LR  - 20230622
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 83
IP  - 12
DP  - 2023 Jun 15
TI  - Proteomic Profiling of Extracellular Matrix Components from Patient Metastases 
      Identifies Consistently Elevated Proteins for Developing Nanobodies That Target 
      Primary Tumors and Metastases.
PG  - 2052-2065
LID - 10.1158/0008-5472.CAN-22-1532 [doi]
AB  - 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. SIGNIFICANCE: 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.
CI  - (c)2023 The Authors; Published by the American Association for Cancer Research.
FAU - Jailkhani, Noor
AU  - Jailkhani N
AUID- ORCID: 0000-0002-4933-1068
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
FAU - Clauser, Karl R
AU  - Clauser KR
AUID- ORCID: 0000-0002-1052-9456
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Mak, Howard H
AU  - Mak HH
AUID- ORCID: 0000-0003-2031-4472
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
FAU - Rickelt, Steffen
AU  - Rickelt S
AUID- ORCID: 0000-0002-5224-7764
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
FAU - Tian, Chenxi
AU  - Tian C
AUID- ORCID: 0000-0002-6737-968X
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
FAU - Whittaker, Charles A
AU  - Whittaker CA
AUID- ORCID: 0000-0002-2400-0094
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
FAU - Tanabe, Kenneth K
AU  - Tanabe KK
AUID- ORCID: 0000-0003-1920-3417
AD  - Division of Gastrointestinal and Oncologic Surgery, Massachusetts General 
      Hospital Cancer Center, Boston, Massachusetts.
FAU - Purdy, Stephen R
AU  - Purdy SR
AUID- ORCID: 0000-0002-3307-1433
AD  - Camelid Immunogenics, Belchertown, Massachusetts.
FAU - Carr, Steven A
AU  - Carr SA
AUID- ORCID: 0000-0002-7203-4299
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Hynes, Richard O
AU  - Hynes RO
AUID- ORCID: 0000-0001-7603-8396
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
AD  - Howard Hughes Medical Institute, Chevy Chase, Maryland.
LA  - eng
GR  - P30 CA014051/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Single-Domain Antibodies)
RN  - 0 (Tenascin)
SB  - IM
MH  - Humans
MH  - *Single-Domain Antibodies
MH  - Proteomics/methods
MH  - *Triple Negative Breast Neoplasms/pathology
MH  - Chromatography, Liquid
MH  - Tandem Mass Spectrometry
MH  - Extracellular Matrix/metabolism
MH  - Tenascin/metabolism
MH  - *Colorectal Neoplasms/pathology
MH  - Tumor Microenvironment
PMC - PMC10267678
EDAT- 2023/04/26 12:42
MHDA- 2023/06/16 06:42
PMCR- 2023/06/15
CRDT- 2023/04/26 10:13
PHST- 2022/05/10 00:00 [received]
PHST- 2022/11/08 00:00 [revised]
PHST- 2023/04/19 00:00 [accepted]
PHST- 2023/06/16 06:42 [medline]
PHST- 2023/04/26 12:42 [pubmed]
PHST- 2023/04/26 10:13 [entrez]
PHST- 2023/06/15 00:00 [pmc-release]
AID - 726121 [pii]
AID - CAN-22-1532 [pii]
AID - 10.1158/0008-5472.CAN-22-1532 [doi]
PST - ppublish
SO  - Cancer Res. 2023 Jun 15;83(12):2052-2065. doi: 10.1158/0008-5472.CAN-22-1532.