A5060593126- Cancer Cells and Metastasis
- Wnt/β-catenin signaling in development and cancer
- Cancer Genomics and Diagnostics
- Cancer-related gene regulation
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Cell Image Analysis Techniques
- Liver physiology and pathology
- Radiomics and Machine Learning in Medical Imaging
- Digestive system and related health
- Hippo pathway signaling and YAP/TAZ
- Advanced Bandit Algorithms Research
- Artificial Intelligence in Healthcare and Education
- BRCA gene mutations in cancer
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- AI in cancer detection
- RNA Interference and Gene Delivery
- 3D Printing in Biomedical Research
- Amyotrophic Lateral Sclerosis Research
- Health and Medical Studies
- Parkinson's Disease Mechanisms and Treatments
- Genetic factors in colorectal cancer
Broad Institute
2021-2025
Heidelberg University
2016-2024
University Hospital Heidelberg
2018-2024
German Cancer Research Center
2016-2024
Medizinische Fakultät Mannheim
2019
DKFZ-ZMBH Alliance
2016-2019
Abstract In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of stem cells. However, how other oncogenic pathways converge on to modulate cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens CRC, we identify MEK1/2 inhibitors as potent activators Wnt/β-catenin signalling. Targeting MEK increases activity different lines murine intestine vivo. Truncating mutations APC generated by CRISPR/Cas9 strongly...
Abstract Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling human diseases. They have heterogeneous morphologies with unclear biological causes relationship to treatment response. Here, we use high-throughput, image-based profiling quantify phenotypes over 5 million individual colorectal cancer after >500 small molecules. Integration data using multi-omics identifies axes morphological variation across organoids: Organoid size is linked IGF1...
Abstract Overcoming cancer drug resistance is a major unmet clinical need as it remains challenging to accurately predict therapeutic sensitivity from baseline tumor and immune profiling. While biopsies refractory disease are routinely obtain for research, upwards of 40% gastroesophageal 70% ovarian patients develop peritoneal carcinomatosis ascites, plentiful, heterogenous molecularly representative sample format that easily accessible since routine drains occur. However, in standard...
Abstract Overcoming cancer drug resistance is a major unmet clinical need as it remains challenging to accurately predict therapeutic sensitivity from baseline tumor and immune profiling. While biopsies refractory disease are routinely obtain for research, upwards of 40% gastroesophageal 70% ovarian patients develop peritoneal carcinomatosis ascites, plentiful, heterogenous molecularly representative sample format that easily accessible since routine drains occur. However, in standard...
Abstract Patient derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling human diseases from primary patient samples. Organoids can be used as models for drug discovery are being explored to guide clinical decision making. have heterogeneous morphologies with unclear biological causes relationship treatment response. Here, we high-throughput, image-based profiling quantify phenotypes over 5 million individual colorectal cancer after more than 500 small...
ABSTRACT Maintenance of homeostatic processes ensure curtailment intestinal tumorigenesis. Inactivating mutations to Adenomatous Polyposis Coli ( Apc ) result in aberrantly activated Wnt signalling and initiates colorectal cancer (CRC) approx. 80% cases, yet our understanding the subcellular mechanisms that modulate dysregulated pathway activity is limited. Here, using a conditional vivo genetic screen, we identify Rab35 GTPase as novel tumour suppressor modulates regional after loss...
Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents a promising treatment strategy for advanced cancers. Here, we exploited the concept synthetic lethality to identify targets that act synergistically histone deacetylase (HDAC) inhibitors reduce growth CRC. We applied pooled CRISPR-Cas9 screen using custom sgRNA library directed against 614 regulators and discovered knockout euchromatic histone-lysine...
The geroscience hypothesis states that a therapy prevents the underlying aging process should prevent multiple related diseases. mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two most validated pathways. Yet, it's largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with novel class N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, identified lipid metabolism centering on SIRT3...
Colorectal cancer (CRC) is characterized by the aberrant activation of cellular signalling pathways, which are frequently caused genetic alterations. Among those affected Wnt plays an essential role for tumorigenesis and maintenance stem cells. However, it unclear how other oncogenic pathways converge on to modulate cell homeostasis in CRC.
Precision oncology, the genetic sequencing of tumors to identify druggable targets, has emerged as standard care in treatment many cancers. Nonetheless, due pace therapy development and variability patient information, designing effective protocols for individual assignment a sample-efficient way remains major challenge. One promising approach this problem is frame precision oncology contextual bandit apply sequential decision-making algorithms designed minimize regret setting. However,...
Einleitung: Etwa 90% der kolorektalen Karzinome (KRK) zeigen eine Überaktivierung des Wnt Signalweges. Bei 80% KRK ist Mutation Wnt-Supressors APC ursächlich, die früh während Karzinogenese auftritt. Neben sind weitere häufig mutierte negative Regulatoren Signalweges bekannt. Jedoch unklar, ob dieser Gene ausreicht, um den Signalweg derartig zu aktivieren, dass Initiation einer möglich ist. Aus murinen Dünn- und Dickdarm isolierte intestinale Organoide ein adäquates Model für Untersuchung...
Abstract To successfully map cancer dependencies, it is essential to conduct genetic and pharmacological screenings in a diversity of cell models. However, existing model development approaches require long periods culture time difficult create long-term models many cancers, greatly limiting the share patient samples that can be studied. enable high-throughput perturbation screens primary cells without an intermediate generation step, we are developing label-free imaging-based platform for...
Abstract High-content screening of cells has become a widespread approach for cellular assays due to its capacity capture complex biological processes. However, conventional cell culture is limited with respect and tissue architecture. Organoids are unique model system the intact diseased intestinal epithelium. The 3D can be used functional study cancer development and, potentially, prospective therapeutic testing drugs in patient derived tumor organoids. Here, we present high-content...
Histon-Deacetylasen (HDAC) regulieren die Transkription von Genen, indem sie Bindungsstärke DNA zu Histonen modifizieren. In gastrointestinalen Tumoren sind HDACs überexprimiert und spielen eine bedeutende Rolle in der Tumorpathogenese. Jedoch zeigen klinische Studien, dass Monotherapie mit HDAC-Inhibitoren beim kolorektalen Karzinom (KRK) keinen Überlebensvorteil erwirkt.
Organoide (Patient Derived Organoids, PDOs) können mit hoher Effizienz aus gastrointestinalen Tumoren gewonnen werden und zeigen hohe Übereinstimmung dem Ursprungsgewebe. Daher sie mittels ex vivo Wirkstofftests zur Etablierung neuer Therapiestrategien nützlich sein.
Abstract Successful mapping of cancer dependencies requires conducting genetic and pharmacological screens in a diversity cell models. However, existing model development approaches require long periods culture time during which evolutionary pressures reduce heterogeneity. It also remains difficult to create long-term models many cancers, greatly limiting the share patient samples that can be studied. These limitations make it challenging large diverse datasets for discovery validation...
Abstract Successful mapping of cancer dependencies requires conducting genetic and drug screens on a diversity models. However, the difficulty in generating long-term models many cancers limits share patient samples that can be studied. Such have likely also lost cellular heterogeneity present original tumor due to vitro propagation. To overcome these limitations, we are developing image-based ex vivo biosensors from early material. Using freshly received gastroesophageal ascites, optimizing...