Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes.

Paul T Winnard,Farhad Vesuna,Jonah Garry,Ramachandra Rao Dasari,Chi Zhang,Ishan Barman,Venu Raman,Jeon Woong Kang

doi:10.18632/oncotarget.14865

Abstract

Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities – a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy.

Highlights

Breast cancer is the most common malignant neoplasm and is the second leading cause of cancer-related death among women in the United States, exceeded only by lung cancer [1]
The 5-year survival for metastatic breast cancer that involves distant organs drops to a dismal 24% [1, 2]. This situation persists because understanding the metastatic progression of breast cancer remains challenging. This is due to several factors including a limited predictability as to which primary tumor is prone to metastatic progression, an inability to monitor the onset of successful metastatic growth, and incomplete knowledge of metabolic, physiologic, and molecular adaptations that allow for the cancer to survive and thrive within the different tissue types [3]
In order to facilitate the tracking of metastatic progression in live mice [27], we engineered triple negative MDA-MB-435 human breast cancer cells [28,29,30,31,32,33,34] to stably express a red fluorescence protein and here designate this cell line: 435-tdT

Summary

Introduction

Breast cancer is the most common malignant neoplasm and is the second leading cause of cancer-related death among women in the United States, exceeded only by lung cancer [1]. The 5-year survival for metastatic breast cancer that involves distant organs drops to a dismal 24% [1, 2]. This situation persists because understanding the metastatic progression of breast cancer remains challenging. This is due to several factors including a limited predictability as to which primary tumor is prone to metastatic progression, an inability to monitor the onset of successful metastatic growth, and incomplete knowledge of metabolic, physiologic, and molecular adaptations that allow for the cancer to survive and thrive within the different tissue types [3]. The current practice of systemic administration of cytotoxic chemotherapy is limited with respect to targeting and drug resistance, which results in numerous adverse side-effects and no cures [5]

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Conclusion