The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia.
School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
Nat Commun. 2022 Aug 6;13(1):4587. doi: 10.1038/s41467-022-32255-7.
The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
肿瘤基质，特别是细胞外基质 (ECM)，是实体瘤的一个显著特征，在塑造肿瘤进展方面起着至关重要的作用。许多促结缔组织增生性肿瘤，包括乳腺癌，涉及到大量的 I 型胶原蛋白的积累。然而，最近人们已经清楚地认识到，基质分子（如胶原蛋白 I）的精确分布和组织同样在肿瘤中与其丰度一样重要。癌相关成纤维细胞 (CAFs) 共存于乳腺癌组织中，并通过重塑 ECM 发挥促肿瘤和抗肿瘤作用。在这里，我们使用脱细胞肿瘤的时间蛋白质组学分析，研究乳腺癌进展过程中不断变化的基质组。我们确定了 4 个关键的基质簇，并指出 XII 型胶原蛋白是调节 I 型胶原蛋白组织的关键成分。通过将我们的蛋白质组学与单细胞转录组学和遗传操作模型相结合，我们展示了 CAF 分泌的 XII 型胶原蛋白如何改变胶原蛋白 I 的组织，以创建支持转移扩散的促侵袭性微环境。最后，我们在患者队列中表明，XII 型胶原蛋白可能代表乳腺癌患者转移复发风险高的一个指标。
