Targeted matrisome analysis identifies thrombospondin-2 and tenascin-C in aligned collagen stroma from invasive breast carcinoma

Lucas A Tomko,Kevin W Eliceiri,Suzanne M Ponik,Kirk C Hansen,Joseph M Szulczewski,Ryan C Hill,Patricia J Keely,Alexander Barrett,Matthew W Conklin

doi:10.1038/s41598-018-31126-w

Abstract

Increasing evidence demonstrates an important role for the extracellular matrix (ECM) in breast cancer progression. Collagen type I, a core constituent of the fibrous ECM, undergoes a significant set of changes that accompany tumor progression, termed Tumor Associated Collagen Signatures (TACS). Late stages of this progression are characterized by the presence of bundled, straight collagen (TACS-2) that become oriented perpendicular to the tumor-stromal boundary (TACS-3). Importantly, the presence of TACS-3 collagen is an independent predictor of poor patient outcome. At present, it remains unclear whether reorganization of the collagen matrix is the consequence of mechanical or compositional tissue remodeling. Here, we identify compositional changes in ECM correlating to collagen fiber reorganization from nineteen normal and invasive ductal carcinoma (IDC) patient biopsies using matrisome-targeted proteomics. Twenty-seven ECM proteins were significantly altered in IDC samples compared to normal tissue. Further, a set of nineteen matrisome proteins positively correlate and five proteins inversely correlate with IDC tissues containing straightened collagen fibers. Tenascin-C and thrombospondin-2 significantly co-localized with aligned collagen fibers in IDC tissues. This study highlights the compositional change in matrisome proteins accompanying collagen re-organization during breast cancer progression and provides candidate proteins for investigation into cellular and structural influences on collagen alignment.

Highlights

Several hallmarks of tumor formation have been proposed and include the evasion of apoptosis, uncontrolled proliferation, self-sufficiency in growth, angiogenesis, and tissue invasion and metastasis[1]
We identified extracellular matrix (ECM) proteins that change between normal mammary tissue and invasive ductal carcinoma (IDC) with respect to collagen fiber organization
Targeted matrisome proteomics reveals a unique signature of ECM and cellular proteins in invasive ductal carcinoma tissues compared to normal breast tissues

Summary

Introduction

Several hallmarks of tumor formation have been proposed and include the evasion of apoptosis, uncontrolled proliferation, self-sufficiency in growth, angiogenesis, and tissue invasion and metastasis[1]. It is unclear whether reorganization of collagen is the consequence of mechanical cues or aberrant ECM deposition In combination, these studies all suggest an underappreciated role for collagen alignment in metastatic disease progression that requires additional investigation of compositional changes in the ECM that accompany collagen reorganization. We identified nineteen ECM proteins that positively correlate and five ECM proteins that inversely correlate with aligned collagen fibers in IDC-s tissues These proteins were further characterized for relevance to disease outcome, structural localization, and association with aligned collagen fibers. Based on these parameters, a signature of four, IDC-s associated proteins that predict metastatic outcome were identified. This study provides a set of candidate ECM proteins for further investigation into the mechanisms that may facilitate collagen fiber organization during tumor progression

Methods

Results

Conclusion