Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway

Harmston, Nathan; Lim, Jun Yi Stanley; Arqués, Oriol; Pálmer, Héctor G.; Petretto, Enrico; Virshup, David M.; Madan, Babita

doi:10.1158/0008-5472.can-20-2129

Cited by 22 publications

(17 citation statements)

References 52 publications

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“…This LGR5+ organoid state was also linked to a reduced sensitivity towards MEK inhibitors, a potential consequence of the already suppressed ERK signaling activity that has been linked to Wnt signaling in colorectal cancer. 50 In fact, pharmacological MEK inhibition led to a shift in organoids towards a LGR5+ state, an effect that we have previously described. 33 The use of MEK inhibitors together with Wnt signaling activating GSK3 inhibitors is an established method to maintain embryonic stem cells in vitro.…”

Section: Discussionmentioning

confidence: 63%

The drug-induced phenotypic landscape of colorectal cancer organoids

Betge

Rindtorff

Sauer

et al. 2019

Preprint

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Patient derived organoids (PDOs) closely resemble individual tumor biology and allow testing of small molecules ex vivo. To systematically dissect compound effects on 3Dorganoids, we developed a high-throughput imaging and quantitative analysis approach. We generated PDOs from colorectal cancer patients, treated them with >500 small molecules and captured >3 million images by confocal microscopy. We developed the software framework SCOPE to measure compound induced reorganization of PDOs. We found diverse, but re-occurring phenotypes that clustered by compound mode-of-action. Complex phenotypes were not congruent with PDO viability and many were specific to subsets of PDO lines or were influenced by recurrent mutations. We further analyzed specific phenotypes induced by compound classes and found GSK3 inhibitors to disassemble PDOs via focal adhesion signaling or that MEK inhibition led to bloating of PDOs by enhancing of stemness. Finally, by viability classification, we show heterogeneous susceptibilities of PDOs to clinical anticancer drugs.

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Section: Discussionmentioning

confidence: 63%

The drug-induced phenotypic landscape of colorectal cancer organoids

Betge

Rindtorff

Sauer

et al. 2019

Preprint

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“…Overall, our results suggest that combination therapy works in two steps. First, Wnt inhibition alone induces premature senescence through RAS‐MAPK activation (Harmston et al , 2020). Second, the reduced expression of DNA repair genes following ETC‐159 treatment causes HR deficiency that, when combined with blockage of PARP‐mediated ssDNA repair by olaparib, leads to an accumulation of dsDNA breaks that accelerates the development of senescence.…”

Section: Resultsmentioning

confidence: 99%

WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer

et al. 2021

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Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt‐addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt‐addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51, are dependent on Wnt/β‐catenin signaling in Wnt‐high cancers, and treatment with a PORCN inhibitor creates a BRCA‐like state. This coherent regulation of DNA repair genes occurs in part via a Wnt/β‐catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt‐high APCmin mutant polyps. Our findings suggest a general paradigm that Wnt/β‐catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.

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“…Organoid models enriched for an LGR5+ stem cell signature presented with a characteristic cystic architecture and were sensitive to inhibitors of Wnt signaling. This LGR5+ organoid state was also linked to a reduced sensitivity towards MEK inhibitors, a potential consequence of the already suppressed ERK signaling activity that has been linked to Wnt signaling in colorectal cancer 54 . In fact, pharmacological MEK inhibition led to a shift in organoids towards a LGR5+ state, an effect that we have previously described 33 .…”

Section: Discussionmentioning

confidence: 99%

The drug-induced phenotypic landscape of colorectal cancer organoids

et al. 2022

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Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them.

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Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway

Cited by 22 publications

References 52 publications

The drug-induced phenotypic landscape of colorectal cancer organoids

The drug-induced phenotypic landscape of colorectal cancer organoids

WNT inhibition creates a BRCA‐like state in Wnt‐addicted cancer

The drug-induced phenotypic landscape of colorectal cancer organoids

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