ProCURE, Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Biomarker and Susceptibility Unit, Program for Cancer Control and Prevention, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
Clin Cancer Res. 2019 Jul 15;25(14):4466-4479. doi: 10.1158/1078-0432.CCR-18-3957. Epub 2019 Apr 12.
The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumor cells for stripping tumors of the protection conferred by the microenvironment.
A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumor cells was performed. We focused on the study of molecules that mediate the communication between both compartments and that entail fibroblasts' activation and the alteration of the sensitivity to chemotherapy. We identified targets for the blocking of the tumor-stroma interaction. Finally, we tested, , the blockade of the tumor-stroma interaction in orthotopic models derived from patients and in models of acquired resistance to oxaliplatin.
IL1β/TGFβ1 are the triggers for fibroblasts' recruitment and conversion into carcinoma-associated fibroblasts (CAF) in colorectal cancer. CAFs then secrete proinflammatory factors that alter sensitivity in tumor cells, activating JAK/STAT and PI3KCA/AKT pathways. Blocking such crosstalk with a neutralizing IL1β antibody and a TGFBR1 inhibitor is relieved by the TAK1-mediated activation of the noncanonical TGFβ pathway, which induces a change in the cytokine/chemokine repertoire that maintains a sustained activation of AKT in tumor cells. TAK1 plus TGFBR1 inhibition blocks IL1β/TGFβ1-mediated fibroblast activation, decreasing the secretion of proinflammatory cytokines. In turn, tumor cells became more sensitive to chemotherapy. the combination of a TAK1 inhibitor plus TGFBR1 inhibitor reduced the metastatic capacity of tumor cells and the recruitment of fibroblasts.
Our findings provide a translational rationale for the inhibition of TAK1 and TGFBR1 to remove the chemoprotection conferred by CAFs.
本研究旨在通过改变正常基质细胞与肿瘤细胞之间的串扰，阻断保护性基质的募集，从而剥夺肿瘤细胞微环境赋予的保护。
对共培养的正常结肠成纤维细胞和结直肠肿瘤细胞进行了转录组分析。我们专注于研究介导这两个隔室之间通讯的分子，这些分子涉及成纤维细胞的激活和对化疗敏感性的改变。我们确定了阻断肿瘤-基质相互作用的靶点。最后，我们在源自患者的原位模型和对奥沙利铂获得性耐药的模型中测试了阻断肿瘤-基质相互作用的效果。
IL1β/TGFβ1 是结直肠癌中成纤维细胞募集和转化为癌相关成纤维细胞（CAF）的触发因素。然后，CAFs 分泌促炎因子，改变肿瘤细胞的敏感性，激活 JAK/STAT 和 PI3KCA/AKT 途径。用中和 IL1β 抗体和 TGFBR1 抑制剂阻断这种串扰，可通过 TAK1 介导的非经典 TGFβ 途径的激活得到缓解，该途径诱导细胞因子/趋化因子谱的改变，从而维持 AKT 在肿瘤细胞中的持续激活。TAK1 加 TGFBR1 抑制阻断了 IL1β/TGFβ1 介导的成纤维细胞激活，减少了促炎细胞因子的分泌。反过来，肿瘤细胞对化疗变得更加敏感。组合使用 TAK1 抑制剂加 TGFBR1 抑制剂可降低肿瘤细胞的转移能力和成纤维细胞的募集。
我们的研究结果为抑制 TAK1 和 TGFBR1 以去除 CAFs 赋予的化学保护提供了转化依据。
