PO.TB09.02 · 肿瘤生物学

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

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

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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