Abstract 2929: Multiplexed somatic genome editing to model and investigate advanced colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is among the deadliest cancers worldwide, with advanced CRC being the leading cause of death. For the development of novel therapy options, it is crucial to investigate mechanisms of advanced CRC in a bona fide way. However, little is known about the impact of distinct genomic alterations on cancer progression. The assessment of the function and role of the putative drivers in tumor progression via sequencing data remains challenging, due to the complexity and possible combinations of the candidates. Hence, genetically engineered mouse models (GEMMs) represent the mainstay for the investigation of the role of oncogenes and tumor suppressor genes in cancer progression. However, particularly in CRC, they are limited by imprecise modeling of cancer-associated changes, challenging scalability, and development of tumors in anatomically incorrect places. To tackle these issues, we developed SOmatic CRISPR-mediated genome Alterations of Tumor suppressors with Exploratory single cell Sequencing (SOCRATES) to analyze advanced CRC. We multiplexed CRISPR-Cas systems, packaged them into lentiviral particles, and delivered them to enterocytes via colonoscopy-guided submucosal injection. With this innovative approach, SOCRATES enables rapid and direct in vivo genome engineering for the modeling of advanced CRC with distinct mutational patterns and the investigation of the cancer cell states and tumor microenvironment (TME) upon editing the genes of interest. Similar to the Greek philosopher Socrates, who established a form of argumentized dialogue between individuals, SOCRATES facilitates the understanding of previously undiscovered communication between cancer cells and TME. We analyzed the influence of the most recurrent tumor suppressor mutations (Fbxw7, Ptprt, Arid1a, Atrx, Atm, Smad4, Pten) on the cancer cell state and TME in advanced CRC. Further, we created a TS-TME interaction atlas and revealed novel mechanistic insights into how the TS mutations rewire cell states and cell-cell communications. With this generated knowledge, SOCRATES will contribute to our understanding of complex tumor ecosystems and foster the improvement of diagnostic and therapeutic approaches. Citation Format: Manuel Mastel, Rene Jackstadt, Jasmin Meier, Gabriele Diamante. Multiplexed somatic genome editing to model and investigate advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2929.