scholarly journals Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5081
Author(s):  
Yuta Adachi ◽  
Ryo Kimura ◽  
Kentaro Hirade ◽  
Hiromichi Ebi
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Activating Mutations ◽  
Survival Signaling ◽  
Kras Protein ◽  
Effector Pathways ◽  
Specific Inhibitors

Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.

scholarly journals The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1239
Author(s):  
Leila Jahangiri ◽  
Tala Ishola ◽  
Perla Pucci ◽  
Ricky M. Trigg ◽  
Joao Pereira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
Repair Capacity ◽  
Mesenchymal Transition ◽  
Cellular Processes

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

scholarly journals Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 5019
Author(s):  
Helena Oliveres ◽  
David Pesántez ◽  
Joan Maurel
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Post Translational Modification ◽  
Mesenchymal Transition ◽  
Igf1r Signaling ◽  
Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

scholarly journals Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition

Oncogene ◽  
2014 ◽  
Vol 34 (30) ◽  
pp. 3908-3916 ◽  
Author(s):  
L Jiang ◽  
L Xiao ◽  
H Sugiura ◽  
X Huang ◽  
A Ali ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition

scholarly journals Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Liang Yu ◽  
Can Cao ◽  
Xu Li ◽  
Mili Zhang ◽  
Qisheng Gu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Micro Rna ◽  
Mesenchymal Transition ◽  
Morphological Alterations ◽  
Cellular Processes ◽  
Senescent Phenotype ◽  
Poor Treatment ◽  
Epithelial Phenotype ◽  
And Control

AbstractThe EMT (epithelial-to-mesenchymal-transition) subtype of gastric cancer (GC) is associated with poor treatment responses and unfavorable clinical outcomes. Despite the broad physiological roles of the micro-RNA (miR)-200 family, they largely serve to maintain the overall epithelial phenotype. However, during late-stage gastric tumorigenesis, members of the miR-200 family are markedly suppressed, resulting in the transition to the mesenchymal state and the acquisition of invasive properties. As such, the miR-200 family represents a robust molecular marker of EMT, and subsequently, disease severity and prognosis. Most reports have studied the effect of single miR-200 family member knockdown. Here, we employ a multiplex CRISPR/Cas9 system to generate a complete miR-200 family knockout (FKO) to investigate their collective and summative role in regulating key cellular processes during GC pathogenesis. Genetic deletion of all miR-200s in the human GC cell lines induced potent morphological alterations, G1/S cell cycle arrest, increased senescence-associated β-galactosidase (SA-β−Gal) activity, and aberrant metabolism, collectively resembling the senescent phenotype. Coupling RNA-seq data with publicly available datasets, we revealed a clear separation of senescent and non-senescent states amongst FKO cells and control cells, respectively. Further analysis identified key senescence-associated secretory phenotype (SASP) components in FKO cells and a positive feedback loop for maintenance of the senescent state controlled by activation of TGF-β and TNF-α pathways. Finally, we showed that miR-200 FKO associated senescence in cancer epithelial cells significantly recruited stromal cells in the tumor microenvironment. Our work has identified a new role of miR-200 family members which function as an integrated unit serving to link senescence with EMT, two major conserved biological processes.

scholarly journals Lumican in Carcinogenesis—Revisited

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1319
Author(s):  
Eirini-Maria Giatagana ◽  
Aikaterini Berdiaki ◽  
Aristidis Tsatsakis ◽  
George N. Tzanakakis ◽  
Dragana Nikitovic
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Cellular Proliferation ◽  
Tumor Biology ◽  
Cancer Prognosis ◽  
Cancer Cell Growth ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Prognosis Marker ◽  
Therapy Target ◽  
Cancer Tissues

Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of the ECM and are established biological mediators. Notably, lumican is involved in cellular processes associated with tumorigeneses, such as EMT (epithelial-to-mesenchymal transition), cellular proliferation, migration, invasion, and adhesion. Furthermore, lumican is expressed in various cancer tissues and is reported to have a positive or negative correlation with tumor progression. This review focuses on significant advances achieved regardingthe role of lumican in the tumor biology. Here, the effects of lumican on cancer cell growth, invasion, motility, and metastasis are discussed, as well as the repercussions on autophagy and apoptosis. Finally, in light of the available data, novel roles for lumican as a cancer prognosis marker,chemoresistance regulator, and cancer therapy target are proposed.

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