João M. Fernandes Neto
A5079694182- Advanced Breast Cancer Therapies
- Cell Image Analysis Techniques
- Cancer Treatment and Pharmacology
- Cancer, Hypoxia, and Metabolism
- Melanoma and MAPK Pathways
- Computational Drug Discovery Methods
- Cancer, Stress, Anesthesia, and Immune Response
- bioluminescence and chemiluminescence research
- Cancer Research and Treatments
- CAR-T cell therapy research
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Microtubule and mitosis dynamics
- Enzyme function and inhibition
- Lung Cancer Treatments and Mutations
- 3D Printing in Biomedical Research
- Histone Deacetylase Inhibitors Research
- Gene Regulatory Network Analysis
- Biological Research and Disease Studies
- Cytokine Signaling Pathways and Interactions
- Cancer-related Molecular Pathways
- RNA regulation and disease
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Genetic factors in colorectal cancer
The Netherlands Cancer Institute
2017-2024
Oncode Institute
2019-2024
Vrije Universiteit Amsterdam
2021
Institut d'Investigació Biomédica de Bellvitge
2021
Cancer Genomics Centre
2017
Senescence is a proliferation arrest that can result from variety of stresses. Cancer cells also undergo senescence, but the stresses provoke cancer to senescence are unclear. Here, we use both functional genetic and compound screens in harboring reporter activated during find targets induce senescence. We show suppression SWI/SNF component SMARCB1 induces melanoma through strong activation MAP kinase pathway. From screen, identified multiple aurora inhibitors as potent inducers RAS mutant...
Abstract Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity such aberrant signaling. Although inhibition signaling has been explored extensively, there is increasing evidence overactivation same can also disrupt cancer cause lethality. We show here protein phosphatase 2A (PP2A) hyperactivates multiple engages responses in colon cells. Genetic compound screens...
Abstract Resistance to targeted cancer drugs is thought result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up complete inhibition, while decreasing on each component acquire resistance mutation. We report here testing this Multiple Low Dose (MLD) therapy model EGFR mutant NSCLC. show that as little 20% individual effective doses sufficient completely block MAPK and proliferation when used 3D...
Abstract Summary: Most experimental cancer drugs ultimately fail during the course of clinical development, contributing to high cost few that are granted regulatory approval. Moreover, approved often deliver only modest benefit patients with advanced disease due development resistance. Here, we discuss opportunities consider promising overcome drug resistance associated interactions between signaling pathways and presence multiple coexisting cell states within tumors distinct...
<div>Abstract<p>Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity such aberrant signaling. Although inhibition signaling has been explored extensively, there is increasing evidence overactivation same can also disrupt cancer cause lethality. We show here protein phosphatase 2A (PP2A) hyperactivates multiple engages responses in colon cells. Genetic...
ABSTRACT Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity such aberrant signaling. While inhibition signaling has been explored extensively, there is increasing evidence overactivation same can also disrupt cancer cause lethality. We show here Protein Phosphatase 2A (PP2A) hyperactivates multiple engages stress responses in colon cells. Genetic compound screens...
Targeted inhibition of aberrant signaling is an important treatment strategy in cancer, but responses are often short-lived. Multi-drug combinations have the potential to mitigate this, avoid toxicity such must be selective and given at low dosages. Here, we present a pipeline identify promising multi-drug combinations. We perturbed isogenic PI3K mutant wild-type cell line pair with limited set drugs recorded their state viability. then reconstructed networks mapped response changes The...
Targeted cancer drugs often elicit powerful initial responses, but generally fail to deliver long-term benefit due the emergence of resistant cells 1,2 . This is thought be consequence strong selective pressure exerted on drug target by a Maximum Tolerated Dose (MTD) 3–5 We hypothesized that partial inhibition multiple components in same oncogenic signalling pathway might add up complete inhibition, while at time decreasing each individual component acquire resistance mutation. report here...
<p>Figure S9: Single-cell RNAseq identify transcriptional signatures downregulated in CRC cells after acquired resistance to the combination of LB-100 and adavosertib UMAP representations HT-29 (A) SW-480 (B) colored by activity scores for indicated pathways. UMAPs sample origin from both cell lines are present left reference. The boxen plots show pathway parental (red) resistant (blue) cells.</p>
<p>Supplementary table 6: Stress-focused drug screens AUC differences in SW-480 cells Area Under the Curve (AUC) from each compound of stress-focused screen presence or absence LB-100. Compounds are ranked by difference between LB-100-treated and untreated samples.</p>
<p>Supplementary table 3: Full list of genes whose knockout attenuated LB-100 toxicity in SW-480 cells the CRISPR-KO screen FDR smaller or equal to 0.25 and log2 fold change greater 1 treated/untreated comparison were criteria for hit selection.</p>
<p>Supplementary table 1: Cancer cell lines with oncogenic drivers The mutational status of the was compiled from ATCC, Catalogue Somatic Mutations in (COSMIC) and Cell Model Passport, Wellcome Trust Sanger Institute, Depmap portal databases.</p>
<p>Supplementary table 4: The composition of the stress-focused drug library Compounds comprising with their respective targets.</p>
<p>Supplementary table 4: The composition of the stress-focused drug library Compounds comprising with their respective targets.</p>
<p>Figure S7: Normal tissues from the orthotopic CRC PDXs are not affected by LB-100, adavosertib, or combination. Representative Hematoxylin & Eosin (H&E) stainings of heart, liver, lung, and spleen PDOX1 treated as indicated. Original magnifications indicated.</p>
<p>Supplementary table 5: Stress-focused drug screens AUC differences in HT-29 cells Area Under the Curve (AUC) from each compound of stress-focused screen presence or absence LB-100. Compounds are ranked by difference between LB-100-treated and untreated samples.</p>
<p>Figure S9: Single-cell RNAseq identify transcriptional signatures downregulated in CRC cells after acquired resistance to the combination of LB-100 and adavosertib UMAP representations HT-29 (A) SW-480 (B) colored by activity scores for indicated pathways. UMAPs sample origin from both cell lines are present left reference. The boxen plots show pathway parental (red) resistant (blue) cells.</p>
<p>Figure S8: Acquired resistance to the combination of LB-100 and adavosertib suppressed malignant traits in CRC models (A) IncuCyte-based proliferation assays from HT-29 SW-480 parental resistant cells absence or presence (LB-100 4 µM + 400 nM). (B) Chromosome counting representative chromosome spreads cells. Nocodazole was added for 3h block mitosis. Cells were harvested by mitotic shake-off spreading. Over 40 (HT-29 HT-29-R) 50 (SW-480 SW-480-R) counted per cell line. Asterisks...
<p>Figure S7: Normal tissues from the orthotopic CRC PDXs are not affected by LB-100, adavosertib, or combination. Representative Hematoxylin & Eosin (H&E) stainings of heart, liver, lung, and spleen PDOX1 treated as indicated. Original magnifications indicated.</p>
<p>Supplementary table 7: Full list of genes whose knockout was selectively toxic in the presence LB-100 SW-480 cells CRISPR-KO screen FDR smaller or equal to 0.25 and log2 fold change -1 treated/untreated comparison were criteria for hit selection.</p>
<p>Supplementary table 2: Full list of genes whose overexpression was selectively toxic in the presence LB-100 HT-29 cells CRISPRa screen FDR smaller or equal to 0.25 and log2 fold change -1 treated/untreated comparison were criteria for hit selection.</p>
<p>Supplementary table 1: Cancer cell lines with oncogenic drivers The mutational status of the was compiled from ATCC, Catalogue Somatic Mutations in (COSMIC) and Cell Model Passport, Wellcome Trust Sanger Institute, Depmap portal databases.</p>
<p>Supplementary table 2: Full list of genes whose overexpression was selectively toxic in the presence LB-100 HT-29 cells CRISPRa screen FDR smaller or equal to 0.25 and log2 fold change -1 treated/untreated comparison were criteria for hit selection.</p>
<p>Supplementary table 6: Stress-focused drug screens AUC differences in SW-480 cells Area Under the Curve (AUC) from each compound of stress-focused screen presence or absence LB-100. Compounds are ranked by difference between LB-100-treated and untreated samples.</p>
<p>Supplementary table 5: Stress-focused drug screens AUC differences in HT-29 cells Area Under the Curve (AUC) from each compound of stress-focused screen presence or absence LB-100. Compounds are ranked by difference between LB-100-treated and untreated samples.</p>