GENESIS: Genome-Encoded Networks Exploring Spatial Immune Signatures

• Název práce v češtině: Role nádorového genomu v aktivaci a prostorovém uspořádání protinádorové imunity
• Název v anglickém jazyce: GENESIS: Genome-Encoded Networks Exploring Spatial Immune Signatures
• Klíčová slova: nádorové mikroprostředí, nádorové mutace, protinádorová imunita, imunoterapie
• Klíčová slova anglicky: tumor microenvironment, tumor mutations, antitumor immunity, immunotherapy
• Akademický rok vypsání: 2024/2025
• Typ práce: disertační práce
• Jazyk práce: angličtina
• Ústav: Ústav imunologie (13-722)
• Vedoucí / školitel: prof. PharmDr. Jitka Palich Fučíková, Ph.D.

Zásady pro vypracování

Hypothesis:
● Consider the entire genome rather than individual gene alterations, identify large genomic rearrangement-like signatures with the potential to resolve aneuploidy in the context of cancer evolution and for prediction of ICI associated signature.
● Generate a unique and access controlled publicly available data set accessible to the research community being in line with the FAIR principle

Seznam odborné literatury

Bibliography
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Předběžná náplň práce

● Aim 1: Resolve the cancer genome not only at single nucleotide level but also on structural variants, genome assembly and epigenetics, alongside matched comprehensive immune composition profiling, to identify evidence indicating that each cancer genome inherits signatures associated with the cell and spatial composition of the TME.
● Aim 2: Apply read-to-use experimental models studying chromosomal rearrangements and structural variations occurring upon selective pressure caused by treatment, tumor localization and immune cells residing at the site of metastatic niche.
● Aim 3: Functionally verify and validate mechanisms reflecting the TME ranging from ‘cold’ to ‘excluded’ tumor development ultimately turning the tumor into a treatment susceptible like TME.

Předběžná náplň práce v anglickém jazyce

Research plan:
In brief, we will use a longitudinal HGSOC cohort to profile the cancer genome together with matched comprehensive immune profiling using high-accurate long-read WGS and sequential multi-color fluorescence imaging, respectively in the collaboration with University of Basel. Unsupervised analysis will be subsequently performed to identify clusters of matched cancer genome signatures with cellular and molecular immune compositions. In parallel, we develop and apply in vitro and in vivo models to dissect mechanisms of cellular and molecular immune escape induced by genomic aberrations beyond gene mutations. In vitro models consist of TP53 mutations, WGD, and subsequent aneuploidy. Apart from the model’s reproducibility which we consider highly relevant addressing the randomness of genomic cancer evolution, the best model will be subjected to prominent features placing cancer cells under selective pressure, always following up by studying the genomic architecture using sequencing technologies balancing costs, throughput, and output. An enrichment of specific genomic signatures (e.g. gain of chr16p in co-cultures with T cells) will be studied in more detail by applying WGS using SMASHseq to understand the consequences of specific genomic aberrations. In parallel, we will trace cancer genomic evolution in vivo using syngeneic ID8 mouse model together with known tertiary lymphoid structure development and sensitivity to ICIs. Finally, we will validate our findings in our conjoint cohorts with several data sets already available (e.g. bulk RNAseq, WESseq, quantified immunophenotypes, and proteomics) and further verify genomic signatures and process either with cryopreserved or viable matched biobanked samples (>600 HGSOC patients) for further in-depth characterisation.