Decoding epigenetic subtypes, resistance mechanisms and vulnerabilities of small cell lung cancer (B05)

R.Hänsel-Hertsch和他的团队将利用他们最新开发的技术来表征在小细胞肺癌获得性耐药中驱动转录因子激活和亚型可塑性的表观遗传机制。在第一个资助期，他们发现在耐化疗的小细胞肺癌中，染色质的可及性和MYC、YAP1、H2A.Z的占有率增加，G-四链二级结构的形成减少，现在他们将通过使用单细胞组学图谱研究更多复发小鼠和患者的标本来验证和证实这一点。然后，他们将测试这一假设，即这些表观遗传变化通过对新发现的转录因子参与的基因操作而导致可操作的脆弱性。该团队将进一步测试，与这些表观遗传变化相关的特定蛋白质是否也适用于使用小分子的治疗干预。

R. Hänsel-Hertsch and his team will employ their newly developed technologies to characterize the epigenetic mechanisms driving transcription factor activation and subtype plasticity in acquired drug resistance in SCLC. In the first funding period, they found increased chromatin accessibility and occupancy of MYC, YAP1, H2A.Z, and decreased G-quadruplex secondary structure formation in chemo-resistant SCLC, which they will now seek to validate and corroborate by studying additional specimens from mice and patients at relapse using single-cell omics profiling. They will then test the hypothesis that these epigenetic alterations cause actionable vulnerabilities by genetic manipulation of newly identified transcription factor involvement. The team will further test, whether particular proteins associated with these epigenetic alterations are also amenable to therapeutic intervention using small molecules.