{"id":{"repo_id":"milano","oai_identifier":"oai:air.unimi.it:2434/1198762"},"canonical_url":"https://search.dev.ndltd.org/etd/milano/oai:air.unimi.it:2434/1198762","repository":{"repo_id":"milano","name":"Università degli Studi di Milano","base_url":"https://air.unimi.it/oai/request"},"display":{"title":"LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA","abstract":"This thesis is the result of my doctoral studies conducted within the Iorio Laboratory at Human Technopole and whose overarching goal has been to design and use data-driven approaches for the integration of molecular and functional-genetics data from preclinical models with the aim of prioritizing subtype-specific therapeutics vulnerabilities in Glioblastoma (GBM). Particularly, in an initial phase of my activities, I have designed and implemented computational methods for reliability and reproducibility assessment of “essentiality profiles” from genome-wide recessive pooled CRISPR-Cas9 screens. Furthermore I have contributed methods and analyses for benchmarking state-of-the-art computational methods aiming at preprocessing CRISPR screening data, and correcting technology-specific biases, such as the tendency of the CRISR-Cas9 system to elicit a gene-independent detrimental effect on cellular survival when targeting genomic copy-number amplified regions (CN bias) and spurious effect due to Cas9-mediated whole chromosome arm truncations (proximity bias). Subsequently, I have focused on the integration of transcriptomics and CRISPR-based genome-editing data for prioritizing potential therapeutic targets that regulate Glioblastoma stem cells (GSCs) morphology and survival, in collaboration with the Kalebic research group. A key result of this collaboration has been the identification of adducin-γ (ADD3), a previously known morpho-regulator of human neural progenitor cells, as a context-specific essential gene in GBM. I further investigated ADD3 expression at the single-cell level in GBM primary tumours, where I found it to be associated with an oligodendrocyte-progenitorlike (OPC-like) signature, suggesting a specific role of ADD3 in this transcriptional subtype. Adopting this specific case as a proof-of-concept, I have then designed an analytical framework that integrates pharmacogenomics and CRISPR genome-editing with single cell RNA sequencing (scRNA-seq) data, leveraging the Cancer 13Dependency Map (DEPMAP) resource. This framework aims to prioritize GBM subtypes’ vulnerabilities upon a broad spectrum of genetics and drugs perturbation, aiding in the identification of new potential targets and therapeutic compounds that may be most effective in reducing viability of specific subtypes.","abstract_html":"This thesis is the result of my doctoral studies conducted within the Iorio Laboratory at Human Technopole and whose overarching goal has been to design and use data-driven approaches for the integration of molecular and functional-genetics data from preclinical models with the aim of prioritizing subtype-specific therapeutics vulnerabilities in Glioblastoma (GBM). Particularly, in an initial phase of my activities, I have designed and implemented computational methods for reliability and reproducibility assessment of “essentiality profiles” from genome-wide recessive pooled CRISPR-Cas9 screens. Furthermore I have contributed methods and analyses for benchmarking state-of-the-art computational methods aiming at preprocessing CRISPR screening data, and correcting technology-specific biases, such as the tendency of the CRISR-Cas9 system to elicit a gene-independent detrimental effect on cellular survival when targeting genomic copy-number amplified regions (CN bias) and spurious effect due to Cas9-mediated whole chromosome arm truncations (proximity bias). Subsequently, I have focused on the integration of transcriptomics and CRISPR-based genome-editing data for prioritizing potential therapeutic targets that regulate Glioblastoma stem cells (GSCs) morphology and survival, in collaboration with the Kalebic research group. A key result of this collaboration has been the identification of adducin-γ (ADD3), a previously known morpho-regulator of human neural progenitor cells, as a context-specific essential gene in GBM. I further investigated ADD3 expression at the single-cell level in GBM primary tumours, where I found it to be associated with an oligodendrocyte-progenitorlike (OPC-like) signature, suggesting a specific role of ADD3 in this transcriptional subtype. Adopting this specific case as a proof-of-concept, I have then designed an analytical framework that integrates pharmacogenomics and CRISPR genome-editing with single cell RNA sequencing (scRNA-seq) data, leveraging the Cancer 13Dependency Map (DEPMAP) resource. This framework aims to prioritize GBM subtypes’ vulnerabilities upon a broad spectrum of genetics and drugs perturbation, aiding in the identification of new potential targets and therapeutic compounds that may be most effective in reducing viability of specific subtypes.","abstract_has_math":false,"creators":["IANNUZZI, RAFFAELE MARIA"],"institution":"Università degli Studi di Milano","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["supervisor: F. Iorio","N. Kalebic","L. Calviello","E. Petsalaki","Iorio","Francesco; Kalebic","Nereo; Calviello","Lorenzo; Petsalaki","Evangelia","R.M. Iannuzzi"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12-16","date_published":"2025-12-16","updated_at":"2026-07-27T20:18:43Z","subjects":["Settore MEDS-02/A - Patologia generale"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess","license:Creative commons","license uri:http://creativecommons.org/licenses/by-sa/4.0/"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2434/1198762","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["supervisor: F. Iorio","N. Kalebic","L. Calviello","E. Petsalaki","Iorio","Francesco; Kalebic","Nereo; Calviello","Lorenzo; Petsalaki","Evangelia","R.M. 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Particularly, in an initial phase of my activities, I have designed and implemented computational methods for reliability and reproducibility assessment of “essentiality profiles” from genome-wide recessive pooled CRISPR-Cas9 screens. Furthermore I have contributed methods and analyses for benchmarking state-of-the-art computational methods aiming at preprocessing CRISPR screening data, and correcting technology-specific biases, such as the tendency of the CRISR-Cas9 system to elicit a gene-independent detrimental effect on cellular survival when targeting genomic copy-number amplified regions (CN bias) and spurious effect due to Cas9-mediated whole chromosome arm truncations (proximity bias). Subsequently, I have focused on the integration of transcriptomics and CRISPR-based genome-editing data for prioritizing potential therapeutic targets that regulate Glioblastoma stem cells (GSCs) morphology and survival, in collaboration with the Kalebic research group. A key result of this collaboration has been the identification of adducin-γ (ADD3), a previously known morpho-regulator of human neural progenitor cells, as a context-specific essential gene in GBM. I further investigated ADD3 expression at the single-cell level in GBM primary tumours, where I found it to be associated with an oligodendrocyte-progenitorlike (OPC-like) signature, suggesting a specific role of ADD3 in this transcriptional subtype. Adopting this specific case as a proof-of-concept, I have then designed an analytical framework that integrates pharmacogenomics and CRISPR genome-editing with single cell RNA sequencing (scRNA-seq) data, leveraging the Cancer 13Dependency Map (DEPMAP) resource. This framework aims to prioritize GBM subtypes’ vulnerabilities upon a broad spectrum of genetics and drugs perturbation, aiding in the identification of new potential targets and therapeutic compounds that may be most effective in reducing viability of specific subtypes."]},{"key":"dc:title","label":"Title","values":["LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA"]}]}],"canonical_facts":{"dc:contributor":["supervisor: F. Iorio","N. Kalebic","L. Calviello","E. Petsalaki","Iorio","Francesco; Kalebic","Nereo; Calviello","Lorenzo; Petsalaki","Evangelia","R.M. 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Furthermore I have contributed methods and analyses for benchmarking state-of-the-art computational methods aiming at preprocessing CRISPR screening data, and correcting technology-specific biases, such as the tendency of the CRISR-Cas9 system to elicit a gene-independent detrimental effect on cellular survival when targeting genomic copy-number amplified regions (CN bias) and spurious effect due to Cas9-mediated whole chromosome arm truncations (proximity bias). Subsequently, I have focused on the integration of transcriptomics and CRISPR-based genome-editing data for prioritizing potential therapeutic targets that regulate Glioblastoma stem cells (GSCs) morphology and survival, in collaboration with the Kalebic research group. A key result of this collaboration has been the identification of adducin-γ (ADD3), a previously known morpho-regulator of human neural progenitor cells, as a context-specific essential gene in GBM. I further investigated ADD3 expression at the single-cell level in GBM primary tumours, where I found it to be associated with an oligodendrocyte-progenitorlike (OPC-like) signature, suggesting a specific role of ADD3 in this transcriptional subtype. Adopting this specific case as a proof-of-concept, I have then designed an analytical framework that integrates pharmacogenomics and CRISPR genome-editing with single cell RNA sequencing (scRNA-seq) data, leveraging the Cancer 13Dependency Map (DEPMAP) resource. This framework aims to prioritize GBM subtypes’ vulnerabilities upon a broad spectrum of genetics and drugs perturbation, aiding in the identification of new potential targets and therapeutic compounds that may be most effective in reducing viability of specific subtypes."],"dc:identifier":["https://hdl.handle.net/2434/1198762"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Milano"],"dc:relation":["numberofpages:147","alleditors:Iorio, Francesco; Kalebic, Nereo; Calviello, Lorenzo; Petsalaki, Evangelia"],"dc:rights":["info:eu-repo/semantics/openAccess","license:Creative commons","license uri:http://creativecommons.org/licenses/by-sa/4.0/"],"dc:subject":["Settore MEDS-02/A - Patologia generale"],"dc:title":["LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-27T20:18:43Z"}