Howard Hughes Medical Institute, Stem Cell Program and the Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, United States.
Elife. 2021 Feb 2;10:e64370. doi: 10.7554/eLife.64370.
Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:; model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, including and . The transcriptional program induced by SATB2 overlaps with known MITFAXL and AQP1NGFR1 drug-resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. In summary, we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in autochthonous tumors.
最近对黑色素瘤的基因组和 scRNA-seq 分析表明，转移没有反复出现的遗传驱动因素，同时确定了与侵袭或耐药性相关的常见转录状态。为了测试转录适应是否可以驱动黑色素瘤的进展，我们利用斑马鱼 mitfa:模型，其中恶性进展的特征是遗传进化最小。我们进行了 80 种表观遗传/转录调节剂的过表达筛选，发现神经嵴-间充质发育调节剂 SATB2 可加速侵袭性黑色素瘤的发展。它的过表达诱导斑马鱼肿瘤和人黑色素瘤细胞系中的侵袭小窝形成和侵袭。SATB2 结合并激活神经嵴调节剂，包括 和 。SATB2 诱导的转录程序与已知的 MITFAXL 和 AQP1NGFR1 耐药状态重叠，并在体内功能上驱动增强的肿瘤增殖和对vemurafenib 的耐药性。总之，我们表明，SATB2 对神经嵴间充质样程序的黑色素瘤转录重排可驱动原位肿瘤的侵袭和耐药性。
