Preston Samuel E J, Bartish Margarita, Richard Vincent R, Aghigh Arash, Gonçalves Christophe, Smith-Voudouris Julian, Huang Fan, Thébault Paméla, Cleret-Buhot Aurélie, Lapointe Réjean, Légaré François, Postovit Lynne-Marie, Zahedi René P, Borchers Christoph H, Miller Wilson H, Del Rincón Sonia V
Department of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada; Gerald Bronfman Department of Oncology, Segal Cancer Centre, Lady Davis Institute and Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Gerald Bronfman Department of Oncology, Segal Cancer Centre, Lady Davis Institute and Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Science for Life Laboratory, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Instituet, Stockholm, Sweden.
Matrix Biol. 2022 Aug;111:264-288. doi: 10.1016/j.matbio.2022.07.003. Epub 2022 Jul 14.
The extracellular matrix (ECM) plays critical roles in breast cancer development. Whether ECM composition is regulated by the phosphorylation of eIF4E on serine 209, an event required for tumorigenesis, has not been explored. Herein, we used proteomics and mouse modeling to investigate the impact of mutating serine 209 to alanine on eIF4E (i.e., S209A) on mammary gland (MG) ECM. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD028953. We discovered that S209A knock-in mice, expressing a non-phosphorylatable form of eIF4E, have less collagen-I deposition in native and tumor-bearing MGs, leading to altered tumor cell invasion. Additionally, phospho-eIF4E deficiency impacts collagen topology; fibers at the tumor-stroma boundary in phospho-eIF4E-deficient mice run parallel to the tumor edge but radiate outwards in wild-type mice. Finally, a phospho-eIF4E-deficient tumor microenvironment resists anti-PD-1 therapy-induced collagen deposition, correlating with an increased anti-tumor response to immunotherapy. Clinically, we showed that collagen-I and phospho-eIF4E are positively correlated in human breast cancer samples, and that stromal phospho-eIF4E expression is influenced by tumor proximity. Together, our work defines the importance of phosphorylation of eIF4E on S209 as a regulator of MG collagen architecture in the tumor microenvironment, thereby positioning phospho-eIF4E as a therapeutic target to augment response to therapy.
细胞外基质（ECM）在乳腺癌发展过程中发挥着关键作用。eIF4E丝氨酸209位点的磷酸化是肿瘤发生所必需的事件，ECM的组成是否受其调控尚未得到研究。在此，我们使用蛋白质组学和小鼠模型来研究将eIF4E上的丝氨酸209突变为丙氨酸（即S209A）对乳腺（MG）细胞外基质的影响。蛋白质组学数据已通过PRIDE合作伙伴存储库存入蛋白质组交换联盟，数据集标识符为PXD028953。我们发现，表达不可磷酸化形式eIF4E的S209A基因敲入小鼠，其天然和荷瘤MG中的I型胶原蛋白沉积较少，导致肿瘤细胞侵袭发生改变。此外，磷酸化eIF4E缺乏会影响胶原蛋白拓扑结构；磷酸化eIF4E缺陷小鼠肿瘤-基质边界处的纤维与肿瘤边缘平行，但在野生型小鼠中向外辐射。最后，磷酸化eIF4E缺陷的肿瘤微环境抵抗抗PD-1治疗诱导的胶原蛋白沉积，这与对免疫治疗的抗肿瘤反应增加相关。在临床上，我们发现I型胶原蛋白与磷酸化eIF4E在人类乳腺癌样本中呈正相关，并且基质磷酸化eIF4E的表达受肿瘤距离的影响。总之，我们的工作确定了eIF4E在S209位点的磷酸化作为肿瘤微环境中MG胶原蛋白结构调节剂的重要性，从而将磷酸化eIF4E定位为增强治疗反应的治疗靶点。
