YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular Subtypes

Mouillet-Richard, Sophie; Laurent‐Puig, Pierre

doi:10.3390/cancers12113160

Cited by 23 publications

(19 citation statements)

References 107 publications

(198 reference statements)

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“…2. Recently, Hippo and Notch pathway components have been related as over-represented in CMS4 and missrepresented in CMS2 (Mouillet-Richard & Laurent-Puig 2020). YAP/TAZ, a crosstalk node between the Hippo and Wnt signalling pathways regulates glucose, lipid, and amino acid metabolism, as well as mitochondrial biogenesis (Koo & Guan 2018).…”

Section: Figurementioning

confidence: 99%

Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes

Gutiérrez-Salmerón

Lucena

Chocarro-Calvo

et al. 2021

Endocrine-Related Cancer

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The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signaling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinemia and hyperleptinemia in prediabetes and excess circulating glucose and lipids in T2D, overcome formidable barriers for tumor development. Increased nutrient availability favours metabolic reprogramming, alters signaling and generate mutations and epigenetic modifications, through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signaling is lost in diabetes. Excess adipose tissue at the origin of T2D, unbalances adipokine (leptin / adiponectin) secretion ratios and function and disrupts the Insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumorigenesis. Disruption of the Insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.

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Section: Figurementioning

confidence: 99%

Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes

Gutiérrez-Salmerón

Lucena

Chocarro-Calvo

et al. 2021

Endocrine-Related Cancer

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“…By contrast, the microenvironment of mesenchymal CMS4 tumours is proinflammatory with prominent activation of complement pathways, immune and stromal infiltration, and increased ECM deposition. In addition, CMS4 tumours are enriched for signatures associated with EMT, TGFβ signalling, angiogenesis [ 237 ], and YAP/TAZ activity [ 316 ]. Hence, CMS4 tumours carry the worst prognosis due to a heightened metastatic propensity and an inherent resistance to chemotherapy and EGFR-blockers [ 237 , 314 , 317 ].…”

Section: Crc Subtypes and Niche-signalling Pathwaysmentioning

confidence: 99%

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

Sphyris

Hodder

Sansom

2021

Cancers

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The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints (“ISC emancipation”) and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.

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“…The "mesenchymal" CMS4 (23% of tumors) is characterized by upregulation of genes involved in the epithelial to mesenchymal transition (EMT), transforming growth factor-β activation and inflammatory microenvironment. In view of the extensive biological differences between these subtypes, the ability to respond to therapies may also be different for each subtype [36,37]. It is important to note that CMS4 tumors present downregulation of all DNA repair pathways, which is attributed to hypoxia and a stem-like phenotype [38].…”

Section: Molecular Classification Of Crc Tumorsmentioning

confidence: 99%

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

Tomasini

Guecheva²,

Leguisamo³

et al. 2021

Cancers

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Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies.

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YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular Subtypes

Cited by 23 publications

References 107 publications

Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes

Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

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