Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Inserm U830, Institut Curie, PSL Research University, 26, rue d'Ulm, F-75005, Paris, France.
Breast Cancer Res. 2020 Jul 14;22(1):76. doi: 10.1186/s13058-020-01311-9.
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.
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).
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.
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.
早期管腔乳腺癌（BC）占新诊断 BC 病例的 70%。其中，无淋巴结转移（分类为 T1N0）的小（<2cm）BC 预后一般较好，但仍有 5%的管腔 T1N0BC 患者发生远处转移复发，最终导致死亡。我们的工作旨在确定这些患者发生远处转移复发的机制。
我们的研究探讨了自主和非自主肿瘤细胞特征在早期管腔 BC 患者远处复发中的作用。我们创建了一个 T1N0 管腔 BC 患者队列（肿瘤大小为 0.5-2cm，无淋巴结转移），其中有远处转移复发的患者（“病例”）和相应的无复发的患者（“对照”）按主要预后因素 1:1 匹配：年龄、分级和增殖。我们通过免疫组织化学进行深入分析，解析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测定，并突出了癌细胞和特定的癌相关成纤维细胞（CAF）亚群之间的新的合作机制。
我们发现特定的 TME 特征与早期管腔 BC 的复发有关。事实上，定量组织学分析显示，“病例”的特征是特定 CAF 亚群（CAF-S1）的大量积聚和 CD4 T 淋巴细胞减少，与其他免疫细胞无关。多变量分析表明，TME 特征，特别是 CAF-S1 富集，与复发显著相关，从而证明了其临床相关性。最后，通过功能分析，我们证明了 CAF-S1 促转移活性是由 CDH11/成骨细胞钙黏蛋白介导的，这与骨是管腔 BC 患者转移的主要部位一致。
这项研究表明，T1N0BC 的远处复发与 CAF-S1 成纤维细胞的存在密切相关。此外，我们确定 CDH11 是 CAF-S1 介导的促转移活性中的关键分子。这与肿瘤细胞无关，是一个新的预后因素。这些结果可以帮助临床医生识别有高复发风险的管腔 BC 患者。针对 CAF-S1 的靶向治疗，如使用抗 FAP 抗体或 CDH11 靶向化合物，可能有助于预防此类激活基质的患者复发。
