PO.TB09.02 · 肿瘤生物学

纵向黑色素瘤样本的多组学分析揭示进化转变和治疗相关的细胞状态转换

Multi-omics analysis of longitudinal melanoma samples reveals evolutionary transitions and therapy-associated cell-state switching

编号 3535 展板 11 时间 4/20 02:00–05:00 区域 Section 33 主讲 Yourong Bao, BS

分会场 Tumor Evolution

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作者与单位 Authors & Affiliations

Yourong Bao¹, Anne Zaremba², Giuseppe Tarantino³, Tuulia Vallius⁴, Mark Woodnorth³, Mariana Lopez Leon⁵, Yingxiao Shi⁵, Zoltan Maliga⁵, Samira Makhzami⁶, Tyler Aprati³, Bojan Karlas⁷, Valerie Glutsch⁸, Bastian Schilling⁹, Jessica Cecile Hassel¹⁰, Carola Berking¹¹, Jochen Utikal¹², Friedegund Meier¹³, Frank Meiss¹⁴, Lucie Heinzerling¹¹, Katharina Kähler¹⁵, Jiajia Chen³, Lisa Zimmer², Antje Sucker², Elisabeth Livingstone², Eva Hadaschik², Christine G. Lian¹⁶, George F. Murphy¹⁷, Yevgeniy R. Semenov⁴, Genevieve Boland¹⁸, Peter Karl Sorger¹, Florian Rambow¹⁹, David Liu³, Dirk Schadendorf²

¹DFCI/Harvard Medical School, Boston, MA,²Department of Dermatology, University Hospital Essen, Essen, Germany,³Dana-Farber Cancer Institute, Boston, MA,⁴Harvard Medical School, Boston, MA,⁵Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA,⁶Department of Applied Computational Cancer Research, University Hospital Essen, Essen, Germany,⁷MGH/Harvard Medical School, Boston, MA,⁸University Medical Center Hamburg-Eppendorf, Hamburg, Germany,⁹Department of Dermatology, University Hospital Frankfurt, Frankfurt, Germany,¹⁰Department of Dermatology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany,¹¹Department of Dermatology, Venerology and Allergology, University Hospital Erlangen, Erlangen, Germany,¹²Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany,¹³Skin Cancer Center at the University Cancer Centre Dresden, National Center for Tumor Diseases, Depa, University Hospital Carl Gustav Carus, Dresden, Germany,¹⁴Department of Dermatology, University of Freiburg, Freiburg, Germany,¹⁵Department of Dermatology, Venerology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Germany,¹⁶Brigham and Women's Hospital, Harvard Medical School, Boston, MA,¹⁷Department of Pathology, Brigham and Women's Hospital, Boston, MA,¹⁸Massachusetts General Hospital, Boston, MA,¹⁹Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, Essen, Germany

摘要 Abstract

中文摘要

背景：黑色素瘤中的移行转移（ITM）与不良预后相关，然而患者表现出差异极大的临床结局，从快速进展到持久缓解不等。为研究这些差异背后的机制，我们对一例在4年内进展至IV期的ITM黑色素瘤患者的连续肿瘤活检进行了多组学分析。方法：使用ABSOLUTE对14个肿瘤的全外显子组测序（WES）进行纯度校正的变异和CNA判定分析。Pyclone和PhylogicNDT基于癌细胞比例（CCF）定义突变簇并推断肿瘤谱系。随后将系统发育图谱与临床元数据整合。对bulk RNA-seq进行基因集富集分析（GSEA），评估谱系相关和时间相关的黑色素瘤特征及转录程序。结果：系统发育重建从一个共同祖先克隆捕获了3个主要谱系（L1：ITM；L2：ITM+远处皮下转移；L3：远处皮肤转移）。抗PD1联合瘤内T-VEC治疗重塑了肿瘤克隆的基因组格局，选择性地有利于L3，其扩展为克隆性，而L1变得无法检出，与治疗相关的选择一致。从L1分支出的L2也表现出持续存活和免疫耐药。RNA-seq显示，在临床免疫干预后，存在从高度分化状态向AXL高表达状态的协调性转变的证据。转录性肿瘤状态异质性随时间增加，且独立于谱系。ITM（L2）和远处（L3）谱系在克隆形成后立即最初都表现出更具侵袭性、间充质样的细胞状态特征，但随后转向更分化的肿瘤状态，有利于细胞增殖和克隆扩增。在临床病程结束时，所有解剖部位的远处病灶均汇聚于一种MITF驱动的、黑色素细胞样的增殖状态。结论：本研究通过来自一例ITM患者的多组学纵向数据重建了肿瘤进化的系统发育图谱，揭示了与转移事件和临床反应异质性相关的关键通路和肿瘤状态变化。下一步，将把个体系统发育树与队列中的其他患者进行比较，以探索肿瘤进展、转移部位和治疗耐药中的瘤内、瘤间和患者间异质性。

查看英文原文 English abstract

Background: In-transit metastasis (ITM) in melanoma is associated with poor prognosis, yet patients show widely variable clinical outcomes from rapid progression to durable responses. To investigate the mechanisms underlying these variations, we performed multi-omics profiling of sequential tumor biopsies from an ITM melanoma patient who progressed to stage IV over 4 years. Methods: Whole-exome sequencing (WES) from 14 tumors was analyzed using ABSOLUTE for purity-adjusted variant and CNA calling. Pyclone and PhylogicNDT defined mutational clusters based on cancer cell fraction (CCF) and inferred tumor lineages. The phylogenetic map was then integrated with clinical metadata. Gene set enrichment analysis (GSEA) on bulk RNA-seq assessed lineage- and time-associated melanoma signatures and transcriptional programs. Results: Phylogenetic reconstruction captured 3 major lineages (L1: ITM; L2: ITM + distant subcutaneous metastases; L3: distant skin metastases) from a common ancestral clone. Combination of anti-PD1 and intralesional T-VEC therapy reshaped the genomic landscape of tumor clones, selectively favoring L3, which expanded into clonality while L1 became undetectable, consistent with therapy-associated selection. L2, branched off L1, also exhibited persistent survival and immune resistance. RNA-seq showed evidence for a coordinated shift from a highly differentiated state towards an AXL-high state following clinical immune intervention. Transcriptional tumor state heterogeneity increased over time, independent of lineages. Both ITM (L2) and distant (L3) lineages initially displayed more invasive, mesenchymal-like cell state profiles immediately following the clone formation, but transitioned towards more differentiated tumor states, benefiting cell proliferation and clonal expansion. By the end of the clinical course, all distant lesions across anatomical sites converged on an MITF-driven, melanocytic-like proliferative state. Conclusion: This study reconstructed a phylogenetic map for tumor evolution through multi-omics, longitudinal data from an ITM patient to reveal key pathways and tumor state changes associated with metastatic events and heterogeneity in clinical responses. In the next step, the individual phylogenetic trees will be compared with other patients in the cohort to explore intra-tumoral, inter-tumoral, and inter-patient heterogeneity in tumor progression, metastasis sites, and resistance to therapy.

利益披露 Disclosure

Y. Bao, None.. A. Zaremba, None.. T. Vallius, None.. M. Lopez Leon, None.. Y. Shi, None.. S. Makhzami, None.. V. Glutsch, None.. B. Schilling, None.. J. C. Hassel, None.. C. Berking, None.. J. Utikal, None.. F. Meier, None.. F. Meiss, None.. L. Heinzerling, None.. K. Kähler, None.. L. Zimmer, None.. A. Sucker, None.. E. Livingstone, None.. E. Hadaschik, None.. G. F. Murphy, None.. Y. R. Semenov, None.. G. Boland, None.. P. K. Sorger, None.. F. Rambow, None.. D. Schadendorf, None.

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