Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
Project description:Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer
Project description:Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.
Project description:These samples are part of a study investigating cancer cell plasticity in colorectal cancer metastasis. Spatial transcriptomics was performed using 10x Genomics Visium on colorectal cancer liver metastatic patient samples.
Project description:Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.
Project description:Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.
Project description:Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.
