Lineage plasticity in cancer: a shared pathway of therapeutic resistance

Quintanal-Villalonga, Àlvaro; Chan, Joseph M.; Yu, Helena A.; Pe’er, Dana; Sawyers, Charles L.; Sen, Triparna; Rudin, Charles M.

doi:10.1038/s41571-020-0340-z

Cited by 339 publications

(305 citation statements)

References 123 publications

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“…Tumor cell conversion into a different phenotype has been associated with therapeutic resistance [4]. Approximately 20% of advanced prostate cancer patients experience cell plasticity and the acquisition of new phenotypes often associated with loss of androgen receptor signaling [35].…”

Section: Discussionmentioning

confidence: 99%

“…Recent theories postulate that as tumor cells display a high plasticity, therapy exposure and environmental signals can induce phenotype switching towards different phenotypes that are associated with drug resistance, a phenomenon named "lineage plasticity" [3,4]. For instance, in 25% of metastatic prostate carcinoma patients treated with anti-androgen therapy, tumor relapses with morphological features of neuroendocrine carcinoma named neuroendocrine prostate cancer (NEPC) [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Sánchez

Vara-Ciruelos

Díaz‐Laviada

2020

Cells

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In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Sánchez

Vara-Ciruelos

Díaz‐Laviada

2020

Cells

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“…Active genomic research has led to the discovery of driver genes/mutations critical to lung cancer [ 31 ]. Molecularly targeted drugs were developed based on these driver genes, and the prognosis of advanced LUAD has greatly improved due to the emergence of molecularly targeted therapeutic agents [ 32 ]. However, even with these therapeutic agents, it is difficult to eliminate cancer cells from patients.…”

Section: Discussionmentioning

confidence: 99%

FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

Mizuno

Tanigawa

Nohata

et al. 2020

Cells

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Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.

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“…556 The contributions made by neuroendocrine trans-differentiation to the resistance to TKIbased therapy in EGFR-mutant NSCLC have been excellently presented in a number of recent reviews. 26,521 The mechanism behind re-activation of developmental programs Although somatic and neoplastic stem cells reside at the top of the lineage hierarchy, extensive studies have shown that, under certain conditions, not all carcinoma types strictly conform to the generally accepted unidirectional hierarchical model of CSC. This results in a phenotypic switching whereby non-CSCs acquire characteristics of CSCs, such as self-renewal capacity and a slowcycling state.…”

Section: Transition Between Non-csc and Csc States Definition And Chamentioning

confidence: 99%

Emerging role of tumor cell plasticity in modifying therapeutic response

Qin

Jiang

Lü

et al. 2020

Sig Transduct Target Ther

169

122

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Resistance to cancer therapy is a major barrier to cancer management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance, the latter of which is the focus that will be discussed here. Such non-mutational processes are largely driven by tumor cell plasticity, which renders tumor cells insusceptible to the drug-targeted pathway, thereby facilitating the tumor cell survival and growth. The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial–mesenchymal transition, acquisition properties of cancer stem cells, and trans-differentiation potential during drug exposure. From observations in various cancers, this concept provides an opportunity for investigating the nature of anticancer drug resistance. Over the years, our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased. This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs, which are likely to improve patient outcomes in clinical practice.

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Lineage plasticity in cancer: a shared pathway of therapeutic resistance

Cited by 339 publications

References 123 publications

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

Emerging role of tumor cell plasticity in modifying therapeutic response

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