Tetrathiomolybdate (TM)-associated copper depletion influences collagen remodeling and immune response in the pre-metastatic niche of breast cancer

Ying L Liu,Dayle Lapolla,Marta Cobham,Lu Ling,Nicholas Willumsen,Naomi Kornhauser,Divya Ramchandani,Eleni Andreopoulou,Anne Moore,Tessa Cigler,Veronica Fitzpatrick,Vivek Mittal,J David Warren,Maureen Ward,Linda T Vahdat,Claudia Fischbach,Cecilie Liv Bager

doi:10.1038/s41523-021-00313-w

Abstract

Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. We sought to elucidate the mechanism of TM by exploring its effects on collagen processing and immune function in the tumor microenvironment (TME). Using an exploratory cohort, we identified markers of collagen processing (LOXL2, PRO-C3, C6M, and C1M) that differed between those with breast cancer versus controls. We measured these collagen biomarkers in TM-treated patients on the phase II study and detected evidence of decreased collagen cross-linking and increased degradation over formation in those without disease compared to those who experienced disease progression. Preclinical studies revealed decreased collagen deposition, lower levels of myeloid-derived suppressor cells, and higher CD4+ T-cell infiltration in TM-treated mice compared with controls. This study reveals novel mechanisms of TM targeting the TME and immune response with potential applications across cancer types.

Highlights

Breast cancer is the most common cancer in women, and women with early stage disease are often treated successfully, metastatic disease is the leading cause of mortality[1].Efforts to prevent tumor metastases are needed, and growing emphasis is being placed on the role of the pre-metastatic niche and the extracellular matrix (ECM) in tumor metastasis[2,3].The ECM refers to the non-cellular component of tissues that dictates cellular polarity and behavior and maintains microarchitecture, structure and function[4]
acquisition performed on BD Fortessa
isolated lung samples after digestion were stimulated with PMA

Summary

Introduction

Breast cancer is the most common cancer in women, and women with early stage disease are often treated successfully, metastatic disease is the leading cause of mortality[1].Efforts to prevent tumor metastases are needed, and growing emphasis is being placed on the role of the pre-metastatic niche and the extracellular matrix (ECM) in tumor metastasis[2,3].The ECM refers to the non-cellular component of tissues that dictates cellular polarity and behavior and maintains microarchitecture, structure and function[4]. Breast cancer is the most common cancer in women, and women with early stage disease are often treated successfully, metastatic disease is the leading cause of mortality[1]. The degradation of old ECM components and the synthesis, deposition, and cross-linking of new ECM components is maintained in a delicate equilibrium[5]. This equilibrium is often lost in cancer, leading to pathological alterations in the composition and architecture of the ECM that facilitate the hallmarks of cancer metastasis[5]. Emerging data suggest that normalizing ECM composition may be critical in combatting metastatic breast cancer[6,7]

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Conclusion