PDF(Pubmed)
Abstract：
Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.
摘要：
导管原位癌（DCIS）是一种异质性乳腺疾病，由于其不可预测的进展为浸润性乳腺癌（IBC），因此治疗仍具有挑战性。当代文献越来越关注乳腺癌进展的细胞外基质（ECM）改变。然而,DCIS中ECM蛋白质组的空间调控与IBC的关系尚待研究。我们假设DCIS和IBC呈现不同的ECM蛋白质组，可以区分这些病理。纯DCIS的组织切片，混合DCIS-IBC，通过多重空间蛋白质组学研究了具有详细病理注释的纯IBC（n=22）。穿过组织，在病理注释区域及其周围的细胞外微环境中检测到1,005种ECM肽。DCIS与IBC病理的比较证明了43种显著改变的ECM肽。值得注意的是,8种纤维状胶原肽可以区分DCIS和IBC，具有很高的特异性和敏感性。病变靶向蛋白质组成像显示个别DCIS病变周围ECM蛋白质组的异质性。多重空间蛋白质组学报道了一种侵袭性癌症场效应，与远端对应的IBC相比,更靠近IBC的DCIS病变与IBC具有更相似的ECM特征。定义ECM蛋白质组微环境提供了与DCIS和IBC相关的新的分子见解。
