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1.
Nat Cell Biol ; 26(7): 1154-1164, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38849541

RESUMEN

Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.


Asunto(s)
Resistencia a Antineoplásicos , Melanoma , Animales , Humanos , Ratones , Aminoacil-ARNt Sintetasas/metabolismo , Aminoacil-ARNt Sintetasas/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Melanoma/patología , Melanoma/enzimología , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Biosíntesis de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Valina/metabolismo , Valina/genética , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nature ; 629(8012): 543-554, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38750233

RESUMEN

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.


Asunto(s)
Metástasis de la Neoplasia , Neoplasias , Animales , Humanos , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Análisis de la Célula Individual , Multiómica , Tipificación Molecular , Reprogramación Celular
3.
Cancer Discov ; 14(4): 610-614, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38571419

RESUMEN

SUMMARY: Cancer is traditionally perceived through a genetic lens, with therapeutic strategies targeting oncogenic driver mutations. We advocate an overarching framework recognizing tumors as comprising driver, passenger, and trailer cell states: Tailoring therapies to simultaneously target driver genetics and cell states may enhance effectiveness and durability. SIGNIFICANCE: We redefine cancer progression by introducing a model that categorizes tumor cells into "driver," "passenger," and "trailer" phenotypes, expanding the focus on genetic aberrations to cellular behavior. This approach offers a roadmap to guide refining therapeutic strategies for more precise and durable cancer treatments that address tumor heterogeneity and plasticity.


Asunto(s)
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patología
4.
Cancer Cell ; 42(4): 623-645.e10, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38490212

RESUMEN

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.


Asunto(s)
Sistemas CRISPR-Cas , Neoplasias , Humanos , Linfocitos T CD8-positivos , Neoplasias/genética
6.
Cell ; 187(1): 166-183.e25, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38181739

RESUMEN

To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.


Asunto(s)
Melanoma , Humanos , Redes Reguladoras de Genes , Inmunoterapia , Melanocitos , Melanoma/tratamiento farmacológico , Melanoma/genética , Factor de Transcripción 4/genética , Microambiente Tumoral
7.
bioRxiv ; 2023 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-38106050

RESUMEN

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment 1 . However, the molecular mechanisms underlying resistance to LGR5 + CSCs depletion in colorectal cancer (CRC) 2,3 remain largely elusive. Here, we unveil the existence of a primitive cell state dubbed the oncofetal (OnF) state, which works in tandem with the LGR5 + stem cells (SCs) to fuel tumor evolution in CRC. OnF cells emerge early during intestinal tumorigenesis and exhibit features of lineage plasticity. Normally suppressed by the Retinoid X Receptor (RXR) in mature SCs, the OnF program is triggered by genetic deletion of the gatekeeper APC. We demonstrate that diminished RXR activity unlocks an epigenetic circuity governed by the cooperative action of YAP and AP1, leading to OnF reprogramming. This high-plasticity state is inherently resistant to conventional chemotherapies and its adoption by LGR5 + CSCs enables them to enter a drug-tolerant state. Furthermore, through phenotypic tracing and ablation experiments, we uncover a functional redundancy between the OnF and stem cell (SC) states and show that targeting both cellular states is essential for sustained tumor regression in vivo . Collectively, these findings establish a mechanistic foundation for developing effective combination therapies with enduring impact on CRC treatment.

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