A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer
A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer
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DOI：
10.1186/s13058-020-01311-9
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发表时间：
2020-07-14
影响因子：
7.4
通讯作者：
Mechta-Grigoriou, Fatima
中科院分区：
文献类型：
--
作者：
Bonneau, Claire;Elies, Antoine;Mechta-Grigoriou, Fatima
背景早期腔性乳腺癌(BC)占新诊断乳腺癌病例的70%。其中无淋巴结转移的小(2 cm以下)结直肠癌(T1N0)研究较少，其预后一般较好。然而，高达5%的腔内T1N0 BC患者复发并伴有远处转移，最终被证明是致命的。我们工作的目的是确定这些患者转移复发的机制。方法我们的研究探讨了自主性和非自主性肿瘤细胞特征在早期腔性BC患者远处复发中所起的作用。我们建立了一组T1N0腔型BC患者(肿瘤在0.5-2厘米之间无淋巴结转移)，有转移复发(“病例”)和相应的“对照”(无复发)在主要预后因素上1：1匹配：年龄、分级和增殖。我们通过免疫组织化学的深入分析，破译了癌细胞及其肿瘤微环境(TME)的不同特征。我们进行了体外功能分析，并强调了癌细胞和癌症相关成纤维细胞(CAF)的一个特定亚群之间合作的新机制。结果我们发现，TME的特异性特征预示着早期腔性BC的复发。事实上，定量组织学分析显示，“病例”的特征是特定的CAF亚群(CAF-S1)显著积聚，CD4(+)T淋巴细胞减少，与免疫细胞没有任何其他联系。在多变量分析中，TME的特征，特别是CAF-S1的丰富，仍然与复发显著相关，从而证明了它们的临床相关性。最后，通过进行功能分析，我们证明了CAF-S1的前转移活性是由CDH11/成骨细胞钙粘附素介导的，这与腔性BC患者的骨骼是主要转移部位一致。结论本研究表明T1N0BC的远处复发与CAF-S1成纤维细胞的存在密切相关。此外，我们发现CDH11在CAF-S1介导的促转移活性中起关键作用。这是独立于肿瘤细胞的，代表了一个新的预后因素。这些结果可以帮助临床医生识别具有高复发风险的腔性BC患者。使用抗FAP抗体或CDH11靶向化合物针对CAF-S1进行靶向治疗可能有助于防止此类间质激活的患者复发。
Background Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. Methods Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). Results We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4(+)T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. Conclusions This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.