The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology

Jillian L Astarita; Shilpa Keerthivasan; Bushra Husain; Yasin Şenbabaoğlu; Erik Verschueren; Sarah Gierke; Victoria C Pham; Sean M Peterson; Cecile Chalouni; Andrew A Pierce; Jennie R Lill; Lino C Gonzalez; Nadia Martinez-Martin; Shannon J Turley

doi:10.1371/journal.pone.0260800

The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology

PLoS One. 2021 Dec 8;16(12):e0260800. doi: 10.1371/journal.pone.0260800. eCollection 2021.

Affiliations

¹ Department of Cancer Immunology, Genentech, South San Francisco, California, United States of America.
² Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, California, United States of America.
³ Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California, United States of America.
⁴ Center for Advanced Light Microscopy, Genentech, South San Francisco, California, United States of America.
⁵ Department of Research Pathology, Genentech, South San Francisco, California, United States of America.

Abstract

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Cancer-Associated Fibroblasts / immunology
Cancer-Associated Fibroblasts / metabolism
Cancer-Associated Fibroblasts / pathology*
Cell Proliferation
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology*
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Isoantigens / genetics
Isoantigens / metabolism*
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Neutrophils / immunology
Neutrophils / metabolism
Prognosis
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*
Survival Rate
Tumor Cells, Cultured
Tumor Microenvironment*

Substances

Biomarkers, Tumor
CD177 protein, human
GPI-Linked Proteins
Isoantigens
Membrane Glycoproteins
PDPN protein, human
Receptors, Cell Surface

Grants and funding

The study was funded by Genentech. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.