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Article ; Online: Bioengineered 'mini-colons' shed light on cancer progression.

Riggi, Nicolò / de Sousa E Melo, Felipe

2024 Volume 629, Issue 8011, Page(s) 292–293

MeSH term(s)	Humans ; Disease Progression ; Animals ; Neoplasms/pathology ; Neoplasms/genetics ; Mice ; Bioengineering/methods
Language	English
Publishing date	2024-04-24
Publishing country	England
Document type	News
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/d41586-024-01018-3
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Article ; Online: Colon Cancer Heterogeneity: Welcome to the RiboZone.

Piskol, Robert / de Sousa E Melo, Felipe

Cell stem cell

2020 Volume 26, Issue 6, Page(s) 797–799

Abstract: In this issue of Cell Stem Cell, Morral et al. (2020) shed new light on the hierarchical organization of cells within colorectal cancer. They show that tumor cells at the apex of this hierarchy reside in particular tumor zones and possess high protein ... ...

Abstract	In this issue of Cell Stem Cell, Morral et al. (2020) shed new light on the hierarchical organization of cells within colorectal cancer. They show that tumor cells at the apex of this hierarchy reside in particular tumor zones and possess high protein synthesis activity. Interference with their biosynthetic activity results in an irreversible growth arrest of CRC.
MeSH term(s)	Colonic Neoplasms ; Colorectal Neoplasms ; DNA, Ribosomal ; Humans ; Neoplastic Stem Cells
Chemical Substances	DNA, Ribosomal
Language	English
Publishing date	2020-06-04
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2020.05.005
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Zs.A 6589: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Synthetic Multivalent Disulfide-Constrained Peptide Agonists Potentiate Wnt1/β-Catenin Signaling via LRP6 Coreceptor Clustering.

Thakur, Avinash K / Miller, Stephen E / Liau, Nicholas P D / Hwang, Sunhee / Hansen, Simon / de Sousa E Melo, Felipe / Sudhamsu, Jawahar / Hannoush, Rami N

ACS chemical biology

2023 Volume 18, Issue 4, Page(s) 772–784

Abstract: Wnt ligands are critical for tissue homeostasis and form a complex with LRP6 and frizzled coreceptors to initiate Wnt/β-catenin signaling. Yet, how different Wnts achieve various levels of signaling activation through distinct domains on LRP6 remains ... ...

Abstract	Wnt ligands are critical for tissue homeostasis and form a complex with LRP6 and frizzled coreceptors to initiate Wnt/β-catenin signaling. Yet, how different Wnts achieve various levels of signaling activation through distinct domains on LRP6 remains elusive. Developing tool ligands that target individual LRP6 domains could help elucidate the mechanism of Wnt signaling regulation and uncover pharmacological approaches for pathway modulation. We employed directed evolution of a disulfide constrained peptide (DCP) to identify molecules that bind to the third β-propeller domain of LRP6. The DCPs antagonize Wnt3a while sparing Wnt1 signaling. Using PEG linkers with different geometries, we converted the Wnt3a antagonist DCPs to multivalent molecules that potentiated Wnt1 signaling by clustering the LRP6 coreceptor. The mechanism of potentiation is unique as it occurred only in the presence of extracellular secreted Wnt1 ligand. While all DCPs recognized a similar binding interface on LRP6, they displayed different spatial orientations that influenced their cellular activities. Moreover, structural analyses revealed that the DCPs exhibited new folds that were distinct from the parent DCP framework they were evolved from. The multivalent ligand design principles highlighted in this study provide a path for developing peptide agonists that modulate different branches of cellular Wnt signaling.
MeSH term(s)	Ligands ; Wnt Proteins/metabolism ; Low Density Lipoprotein Receptor-Related Protein-6/metabolism ; beta Catenin/metabolism ; Protein Binding ; Wnt Signaling Pathway ; Peptides/pharmacology ; Peptides/metabolism
Chemical Substances	Ligands ; Wnt Proteins ; Low Density Lipoprotein Receptor-Related Protein-6 ; beta Catenin ; Peptides
Language	English
Publishing date	2023-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.2c00753
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Article ; Online: Cellular Plasticity in Intestinal Homeostasis and Disease.

de Sousa E Melo, Felipe / de Sauvage, Frederic J

Cell stem cell

2018 Volume 24, Issue 1, Page(s) 54–64

Abstract: The intestinal epithelium is one the fastest renewing tissues in mammals and is endowed with extensive adaptability. The more traditional view of a hierarchical organization of the gut has recently given way to a more dynamic model in which various cell ... ...

Abstract	The intestinal epithelium is one the fastest renewing tissues in mammals and is endowed with extensive adaptability. The more traditional view of a hierarchical organization of the gut has recently given way to a more dynamic model in which various cell types within the intestinal epithelium can de-differentiate and function as an alternative source of stem cells upon tissue damage and stress conditions such as inflammation and tumorigenesis. Here, we will review the mechanistic principles and key players involved in intestinal plasticity and discuss potential therapeutic implications of cellular plasticity in regenerative medicine and cancer.
MeSH term(s)	Animals ; Carcinogenesis/pathology ; Cell Plasticity ; Homeostasis ; Humans ; Intestinal Mucosa/cytology ; Regenerative Medicine ; Signal Transduction
Language	English
Publishing date	2018-12-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2018.11.019
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Article: Wnt Signaling in Cancer Stem Cell Biology.

de Sousa E Melo, Felipe / Vermeulen, Louis

Cancers

2016 Volume 8, Issue 7

Abstract: Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt ... ...

Abstract	Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.
Language	English
Publishing date	2016-06-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers8070060
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Article ; Online: Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.

Kschonsak, Yvonne T / Gao, Xinxin / Miller, Stephen E / Hwang, Sunhee / Marei, Hadir / Wu, Ping / Li, Yanjie / Ruiz, Karen / Dorighi, Kristel / Holokai, Loryn / Perampalam, Pirunthan / Tsai, Wen-Ting K / Kee, Yee-Seir / Agard, Nicholas J / Harris, Seth F / Hannoush, Rami N / de Sousa E Melo, Felipe

Cell chemical biology

2023

Abstract: Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate ... ...

Abstract	Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.
Language	English
Publishing date	2023-12-05
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.11.006
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Article ; Online: Modeling Colorectal Cancer Progression Through Orthotopic Implantation of Organoids.

de Sousa E Melo, Felipe / Harnoss, Jonathan M / Kljavin, Noelyn / Scott, Ryan / Sohn, Catherine / Leong, Kevin G / de Sauvage, Frederic J

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2171, Page(s) 331–346

Abstract: Colorectal cancer (CRC) related death has often been attributed to the presence of metastatic disseminated disease. A concise understanding of the molecular mechanism(s) that drive metastatic progression is therefore needed but has thus far been hampered ...

Abstract	Colorectal cancer (CRC) related death has often been attributed to the presence of metastatic disseminated disease. A concise understanding of the molecular mechanism(s) that drive metastatic progression is therefore needed but has thus far been hampered by the limited number of CRC mouse models that progress toward this disease stage. In addition, preclinical evaluation of therapeutic modalities aimed at managing metastatic disease also rests on the availability of relevant in vivo models that faithfully recapitulate the key molecular features of metastatic human CRC. To overcome these limitations, we have recently developed methodologies that enable the study of CRC progression at relevant orthotopic sites. Here, we provide a detailed methodology that describes the injection of CRC derived cell lines and organoids directly into the colorectal mucosa. This results in the growth of a single tumor mass within the colon, that can spontaneously metastasize to the liver. Furthermore, we also present a surgical procedure to directly inject cells into the portal venous circulation to induce CRC tumor growth in the liver without the requirement of a primary tumor.
MeSH term(s)	Animals ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Disease Models, Animal ; Humans ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Organoids/cytology ; Organoids/metabolism ; Xenograft Model Antitumor Assays
Language	English
Publishing date	2020-07-23
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0747-3_23
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Article ; Online: Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling.

Hansen, Simon / Zhang, Yingnan / Hwang, Sunhee / Nabhan, Ahmad / Li, Wanqing / Fuhrmann, Jakob / Kschonsak, Yvonne / Zhou, Lijuan / Nile, Aaron H / Gao, Xinxin / Piskol, Robert / de Sousa E Melo, Felipe / de Sauvage, Frederic J / Hannoush, Rami N

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 46, Page(s) e2207327119

Abstract: Developing peptide-based tools to fine-tune growth signaling pathways, in particular molecules with exquisite selectivity and high affinities, opens up opportunities for cellular reprogramming in tissue regeneration. Here, we present a library based on ... ...

Abstract	Developing peptide-based tools to fine-tune growth signaling pathways, in particular molecules with exquisite selectivity and high affinities, opens up opportunities for cellular reprogramming in tissue regeneration. Here, we present a library based on cystine-knot peptides (CKPs) that incorporate multiple loops for randomization and selection via directed evolution. Resulting binders could be assembled into multimeric structures to fine-tune cellular signaling. An example is presented for the Wnt pathway, which plays a key role in the homeostasis and regeneration of tissues such as lung, skin, and intestine. We discovered picomolar affinity CKP agonists of the human LPR6 receptor by exploring the limits of the topological manipulation of LRP6 dimerization. Structural analyses revealed that the agonists bind at the first β-propeller domain of LRP6, mimicking the natural Wnt inhibitors DKK1 and SOST. However, the CKP agonists exhibit a different mode of action as they amplify the signaling of natural Wnt ligands but do not activate the pathway by themselves. In an alveolosphere organoid model, the CKP agonists induced alveolar stem cell activity. They also stimulated growth in primary human intestinal organoids. The approach described here advances the important frontier of next-generation agonist design and could be applied to other signaling pathways to discover tunable agonist ligands.
MeSH term(s)	Humans ; Wnt Signaling Pathway ; beta Catenin/metabolism ; Low Density Lipoprotein Receptor-Related Protein-6/genetics ; Low Density Lipoprotein Receptor-Related Protein-6/metabolism ; Wnt Proteins/metabolism ; Cystine ; Ligands ; Peptides
Chemical Substances	beta Catenin ; Low Density Lipoprotein Receptor-Related Protein-6 ; Wnt Proteins ; Cystine (48TCX9A1VT) ; Ligands ; Peptides
Language	English
Publishing date	2022-11-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2207327119
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Article ; Online: Axing Wnt signals.

De Sousa E Melo, Felipe / Medema, Jan Paul

Cell research

2011 Volume 22, Issue 1, Page(s) 9–11

MeSH term(s)	Animals ; Axin Signaling Complex/genetics ; Axin Signaling Complex/metabolism ; Cell Differentiation ; Cytoplasm/genetics ; Cytoplasm/metabolism ; Homeostasis ; Humans ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptional Activation ; Wnt Signaling Pathway ; beta Catenin/genetics ; beta Catenin/metabolism
Chemical Substances	Axin Signaling Complex ; Transcription Factors ; beta Catenin
Language	English
Publishing date	2011-08-30
Publishing country	England
Document type	Journal Article
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/cr.2011.141
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Article ; Online: ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.

Johnson, Radia M / Qu, Xueping / Lin, Chu-Fang / Huw, Ling-Yuh / Venkatanarayan, Avinashnarayan / Sokol, Ethan / Ou, Fang-Shu / Ihuegbu, Nnamdi / Zill, Oliver A / Kabbarah, Omar / Wang, Lisa / Bourgon, Richard / de Sousa E Melo, Felipe / Bolen, Chris / Daemen, Anneleen / Venook, Alan P / Innocenti, Federico / Lenz, Heinz-Josef / Bais, Carlos

Nature communications

2022 Volume 13, Issue 1, Page(s) 5478

Abstract: Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for ... ...

Abstract	Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.
MeSH term(s)	Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/therapeutic use ; Cetuximab/adverse effects ; Cetuximab/pharmacology ; Cetuximab/therapeutic use ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; DNA-Binding Proteins/genetics ; Drug Resistance, Neoplasm/genetics ; Humans ; Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Transcription Factors/genetics
Chemical Substances	ARID1A protein, human ; Antineoplastic Agents, Immunological ; DNA-Binding Proteins ; Transcription Factors ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Cetuximab (PQX0D8J21J)
Language	English
Publishing date	2022-09-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33172-5
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