Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives

Saunders, Nicholas A.; Simpson, Fiona; Thompson, Erik W.; Hill, Michelle M.; Endo‐Munoz, Liliana; Leggatt, Graham R.; Minchin, Rodney F.; Guminski, Alexander

doi:10.1002/emmm.201101131

Cited by 223 publications

(206 citation statements)

References 79 publications

(140 reference statements)

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“…In addition to heterogeneity across tumors from different patients, intratumor heterogeneity adds another level of complexity. Minor subpopulations of cancer cells can harbor aberrations that are associated with resistance to therapy and tumor progression (6)(7)(8). Thus, treatments may be effective against the majority of the tumor, but a small population of resistant cells can cause the persistence, recrudescence, or recurrence of cancer that is refractory to further treatment.…”

mentioning

confidence: 99%

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Lee

López-Díaz

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

162

150

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The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drugtolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.

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mentioning

confidence: 99%

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Lee

López-Díaz

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

162

150

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“…Intratumoral diversity has emerged over the past years as a promising predictor for cancer initiation (Maley et al 2006), progression (Park et al 2010), and chemotherapy resistance (Saunders et al 2012). Since diagnostic biopsies typically sample only a small portion of the lesion, inferences about total diversity rely heavily on the accuracy of available population genetic models (Beerenwinkel et al 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Studying this issue is thus clinically relevant because genetic diversity will influence the immediate evolution of resistant populations, including response to second-line therapy, evasion of the immune response, or host recolonization (Lipsitch and Levin 1997;Woolhouse et al 2001;Tenaillon et al 2010). Indeed, in the related field of cancer evolution, consideration of genetic diversity within premalignant lesions and tumors is becoming increasingly recognized as key to improving diagnosis, prognosis, and the choice of optimal treatment strategies (Maley et al 2006;Park et al 2010;Saunders et al 2012).…”

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confidence: 99%

Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria

2016

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Any pathogen population sufficiently large is expected to harbor spontaneous drug-resistant mutants, often responsible for disease relapse after antibiotic therapy. It is seldom appreciated, however, that while larger populations harbor more mutants, the abundance distribution of these mutants is expected to be markedly uneven. This is because a larger population size allows early mutants to expand for longer, exacerbating their predominance in the final mutant subpopulation. Here, we investigate the extent to which this reduction in evenness can constrain the genetic diversity of spontaneous drug resistance in bacteria. Combining theory and experiments, we show that even small variations in growth rate between resistant mutants and the wild type result in orders-ofmagnitude differences in genetic diversity. Indeed, only a slight fitness advantage for the mutant is enough to keep diversity low and independent of population size. These results have important clinical implications. Genetic diversity at antibiotic resistance loci can determine a population's capacity to cope with future challenges (i.e., second-line therapy). We thus revealed an unanticipated way in which the fitness effects of antibiotic resistance can affect the evolvability of pathogens surviving a drug-induced bottleneck. This insight will assist in the fight against multidrug-resistant microbes, as well as contribute to theories aimed at predicting cancer evolution.

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“…Increased expression of certain genes and reduction of others constantly change their dynamic balance, which determines not only the degree of heterogeneity, but also the level of sensitivity to therapy [5].…”

Section: Introductionmentioning

confidence: 99%

Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells

Чехун¹,

Lukianova²,

Demash³

et al. 2013

CellBio

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Effects of the nanocomposite and its components (magnetic fluid, cisplatin) on the level of endogenous iron exchange and the key links of genetic and epigenetic regulation of apoptotic program of sensitive and resistant MCF-7 cells were examined. We showed genetic and epigenetic mechanisms of action of nanocomposite of magnetic fluid and cisplatin. Nanocomposite caused elevation of number of cells in apoptosis in sensitive and especially resistant MCF-7 cells compared to cisplatin alone. It was proved that impact of nanocomposite on MCF-7/S and MCF-7/DDP cells caused more significant changes in expression of apoptosis regulators p53, Bcl-2 and Bax. We also suggested that changes in endogenous iron homeostasis and activation of free radical processes caused significant impact on apoptosis. Those changes included changes in methylation and expression of transferrin, its receptors, ferritin heavy and light chains (predominantly in resistant cell line), which caused activation of free radical synthesis and development of oxidative stress. We also showed that nanocomposite impact resulted into significant changes in expression of miRNA-34a and miRNA-200b, which regulated apoptosis, cell adhesion, invasion and activity of ferritin heavy chains gene. Thus, use of nanocomposite containing cisplatin and ferromagnetic as exogenous source of Fe ions caused changes of endogenous iron levels in sensitive and resistant cells allowing to increase specific activity of cytostatics and overcome factors, which promoted MDR development. Pharmacocorrection of endogenous iron metabolism allowed increasing antitumor activity of cisplatin and overcoming drug resistance.

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Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives

Cited by 223 publications

References 79 publications

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria

Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells

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