Unbiased peptoid combinatorial cell screen identifies plectin protein as a potential biomarker for lung cancer stem cells

Aaron C Raymond,John D Minna,Luc Girard,D Gomika Udugamasooriya,Boning Gao

doi:10.1038/s41598-019-51004-3

Abstract

Tumors often contain a small subset of drug-resisting, self-renewing, and highly metastatic cells called tumor initiating cells or cancer stem cells (CSCs). To develop new approaches to detecting and targeting lung cancer CSCs, we applied an “unbiased” peptoid combinatorial cell screen to identify highly specific ligands that bind a CSC subpopulation of non-small cell lung cancer cells (defined by Aldefluor positivity), but not the remaining aldefluor negative cancer cells from the same preclinical model. One of the ‘hit’ peptoids bound to plectin, a structural protein, predominantly expressed intracellularly, but whose localization on the cell surface is linked to tumor invasion and metastasis. Our studies show both genotypic and phenotypic correlations between plectin and lung CSCs, as well as association of high plectin mRNA expression with poor patient survival in lung adenocarcinoma, potentially identifying plectin as a biomarker for lung CSCs.

Highlights

Tumors often contain a small subset of drug-resisting, self-renewing, and highly metastatic cells called tumor initiating cells or cancer stem cells (CSCs)
We have used our on-bead two-color (OBTC) approach to screen a large peptoid library and identified the PCS2 peptoid that bound the ALDH+ subset of H358 non-small cell lung cancer (NSCLC) cells, which previously has been shown to be enriched in CSCs21
We were able to demonstrate that PCS2 binds to plectin, which normally is expressed intracellularly, but in cancer cells can be expressed on the cell surface

Summary

Introduction

Tumors often contain a small subset of drug-resisting, self-renewing, and highly metastatic cells called tumor initiating cells or cancer stem cells (CSCs). Developing treatment strategies targeting CSCs remains a challenge, due to the paucity of reliable biomarkers identifying such subpopulations To circumvent this limitation, we applied our on-bead two-color (OBTC) combinatorial cell screen[4–6] technology to unbiasedly select peptidomimetic (peptoids: oligo-N-substituted glycines) ligands that target biomarkers on the CSC surface of a preclinical model of non-small cell lung cancer (NSCLC), while not binding to the remaining cancer cells in the same model. We applied our on-bead two-color (OBTC) combinatorial cell screen[4–6] technology to unbiasedly select peptidomimetic (peptoids: oligo-N-substituted glycines) ligands that target biomarkers on the CSC surface of a preclinical model of non-small cell lung cancer (NSCLC), while not binding to the remaining cancer cells in the same model Using this approach we identified plectin as a new lung CSC biomarker and potential therapeutic target. These plectin (+) subpopulations are highly clonogenic and enriched for cell migration and other properties of CSCs, and variably correlate with expression of previously described CSC markers such as ALDH1A3, CD44 and SOX2

Methods

Results

Conclusion