Proteomic landscape of multi-layered breast cancer internal tumor heterogeneity

Abstract

SummaryDespite extensive research, internal tumor heterogeneity presents enormous challenges to achieve complete therapeutic responses. Changes in protein expression are central determinants of cancer phenotypes that reflect potential therapeutic targets. However, previous proteomic studies did not address internal heterogeneity, therefore, masked the necessary spatial resolution to achieve a comprehensive understanding of cancer complexity. Here we present the first large-scale multi-focal breast cancer proteomic study of 330 tumor regions which associated cancer cell function, pathological parameters, and spatial localization of each tumor region. We found marked internal proteomic heterogeneity even within tumors presenting homogeneous receptor expression. Additionally, analysis of the internal heterogeneity, based on coexisting receptor expression or histological patterns in single tumors, showed significant functional differences between homogeneous and heterogeneous tumors related to cancer metabolism, immunogenicity, and proliferation. We anticipate that this study will serve as a starting point towards the development of improved cancer therapy and diagnostics.

Unbiased spatial proteomics with single-cell resolution in tissues

“…Importantly, PTMs are also perfectly preserved over decades in these blocks, awaiting measurement (Friedrich et al, 2021;Ostasiewicz et al, 2010). Efficient protocols have enabled the streamlined analysis of macro or laser microdissected FFPE tissues (Coscia et al, 2020;Griesser et al, 2020;Zhu et al, 2018bZhu et al, , 2019, leading to insights into tumor heterogeneity (Mardamshina et al, 2021;Xu et al, 2018) and discovery of a novel biomarker of longterm survival following chemotherapy in ovarian cancer (Coscia et al, 2018). Notably, even decades old FFPE material can be analyzed, and functional biomarkers have also been found in the proteins of the extracellular matrix (Eckert et al, 2019).…”