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1.
EMBO J ; 39(18): e103932, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32965059

RESUMEN

Wnt/ß-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce ß-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing ß-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.


Asunto(s)
Quinasa de la Caseína I/metabolismo , Neoplasias/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Vía de Señalización Wnt , Quinasa de la Caseína I/genética , Células HEK293 , Humanos , Neoplasias/genética , Neoplasias/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , beta Catenina/genética , beta Catenina/metabolismo
2.
Curr Opin Cell Biol ; 86: 102311, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38176349

RESUMEN

Tissue-resident myeloid cells sense and transduce mechanical signals such as stiffness, stretch and compression. In the past two years, our understanding of the mechanosensitive signalling pathways in myeloid cells has significantly expanded. Moreover, it is increasingly clear which mechanical signals induce myeloid cells towards a pro- or anti-inflammatory phenotype. This is especially relevant in the context of altered matrix mechanics in immune-related pathologies or in the response to implanted biomaterials. A detailed understanding of myeloid cell mechanosensing may eventually lead to more effective cell-based immunotherapies for cancer, the development of mechanically inspired therapies to target fibrosis, and the engineering of safer implants. This review covers these recent advances in the emerging field of mechanoimmunology of myeloid cells.


Asunto(s)
Neoplasias , Transducción de Señal , Humanos , Neoplasias/terapia , Biofisica , Células Mieloides , Mecanotransducción Celular/fisiología
3.
Life Sci Alliance ; 7(9)2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38969364

RESUMEN

The transmembrane E3 ligases RNF43 and ZNRF3 perform key tumour suppressor roles by inducing endocytosis of members of the Frizzled (FZD) family, the primary receptors for WNT. Loss-of-function mutations in RNF43 and ZNRF3 mediate FZD stabilisation and a WNT-hypersensitive growth state in various cancer types. Strikingly, RNF43 and ZNRF3 mutations are differentially distributed across cancer types, raising questions about their functional redundancy. Here, we compare the efficacy of RNF43 and ZNRF3 of targeting different FZDs for endocytosis. We find that RNF43 preferentially down-regulates FZD1/FZD5/FZD7, whereas ZNRF3 displays a preference towards FZD6. We show that the RNF43 transmembrane domain (TMD) is a key molecular determinant for inducing FZD5 endocytosis. Furthermore, a TMD swap between RNF43 and ZNRF3 re-directs their preference for FZD5 down-regulation. We conclude that RNF43 and ZNRF3 preferentially down-regulate specific FZDs, in part by a TMD-dependent mechanism. In accordance, tissue-specific expression patterns of FZD homologues correlate with the incidence of RNF43 or ZNRF3 cancer mutations in those tissues. Consequently, our data point to druggable vulnerabilities of specific FZD receptors in RNF43- or ZNRF3-mutant human cancers.


Asunto(s)
Endocitosis , Receptores Frizzled , Ubiquitina-Proteína Ligasas , Receptores Frizzled/metabolismo , Receptores Frizzled/genética , Humanos , Endocitosis/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Células HEK293 , Mutación , Vía de Señalización Wnt/genética , Regulación hacia Abajo/genética
4.
Neoplasia ; 23(1): 149-157, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33321449

RESUMEN

The discovery that cancer cells discharge vast quantities of extracellular vesicles (EVs), underscored the explosion of the EV field. A large body of evidence now supports their onco-functionality in an array of contexts; stromal crosstalk, immune evasion, metastatic site priming, and drug resistance - justifying therapeutic intervention. The current bottleneck is a lack of clear understanding of why and how EV biogenesis ramps up in cancer cells, and hence where exactly avenues for intervention may reside. We know that EVs also play an array of physiological roles, therefore effective anticancer inhibition requires a target distinct enough from physiology to achieve efficacy. Taking the perspective that EV upregulation may be a consequence of the tumor landscape, we examine classic mutational events and tumor characteristics for EV regulators. All the while, aiming to illuminate topics worth further research in therapeutic development.


Asunto(s)
Vesículas Extracelulares/metabolismo , Neoplasias/metabolismo , Biomarcadores , Comunicación Celular , Susceptibilidad a Enfermedades , Metabolismo Energético , Exosomas/metabolismo , Regulación de la Expresión Génica , Humanos , Neoplasias/etiología , Neoplasias/patología , Oncogenes , Transducción de Señal , Microambiente Tumoral
5.
Cancers (Basel) ; 12(7)2020 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-32664619

RESUMEN

Colorectal cancer (CRC) is one of the most frequent and deadly forms of cancer. About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum. The majority of these patients cannot be cured despite steady advances in treatment options. Immunotherapies are currently not widely applicable for this disease, yet show potential in preclinical models and clinical translation. The tumour microenvironment (TME) has emerged as a key factor in CRC metastasis, including by means of immune evasion-forming a major barrier to effective immuno-oncology. Several approaches are in development that aim to overcome the immunosuppressive environment and boost anti-tumour immunity. Among them are vaccination strategies, cellular transplantation therapies, and targeted treatments. Given the complexity of the system, we argue for rational design of combinatorial therapies and consider the implications of precision medicine in this context.

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