Drug resistance: origins, evolution and characterization of genomic clones and the tumor ecosystem to optimize precise individualized therapy

Kyrochristos, Ioannis D; Ziogas, Dimosthenis; Roukos, Dimitrios H

doi:10.1016/j.drudis.2019.04.008

Cited by 29 publications

(16 citation statements)

References 89 publications

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“…Tumor cell plasticity is a key challenge for current cancer therapy (Boumahdi and de Sauvage, 2020). Extensive genetic heterogeneity within tumors reinforces tumor evolution, and thereby supports metastatic spread and drug resistance of cancer cells (McGranahan and Swanton, 2017;Dagogo-Jack and Shaw, 2018;Kyrochristos et al, 2019). Understanding the processes yielding profound genetic diversity within the same tumor, as well as between the primary and metastatic pairs is a fundamental issue and of immediate research interest while cancer cell metastasis and drug resistance are winning out and offsetting the current cancer therapy protocols at large.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Saydam

2021

Front. Cell Dev. Biol.

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Cancer metastasis is the major cause of death from cancer (Massague and Obenauf, 2016; Steeg, 2016). The extensive genetic heterogeneity and cellular plasticity of metastatic tumors set a prime barrier for the current cancer treatment protocols (Boumahdi and de Sauvage, 2020). In addition, acquired therapy resistance has become an insurmountable obstacle that abolishes the beneficial effects of numerous anti-cancer regimens (De Angelis et al., 2019; Boumahdi and de Sauvage, 2020). Here we report that deficiency of Ku leads to the exploitation of host cells in human cancer cell line models. We found that, upon conditional deletion of XRCC6 that codes for Ku70, HCT116 human colorectal cancer cells gain a parasitic lifestyle that is characterized by the continuous cycle of host cell exploitation. We also found that DAOY cells, a human medulloblastoma cell line, innately lack nuclear Ku70/Ku86 proteins and utilize the host-cell invasion/exit mechanism for maintenance of their survival, similarly to the Ku70 conditionally-null HCT116 cells. Our study demonstrates that a functional loss of Ku protein promotes an adaptive, opportunistic switch to a parasitic lifestyle in human cancer cells, providing evidence for a previously unknown mechanism of cell survival in response to severe genomic stress. We anticipate that our study will bring a new perspective for understanding the mechanisms of cancer cell evolution, leading to a shift in the current concepts of cancer therapy protocols directed to the prevention of cancer metastasis and therapy resistance.

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Section: Introductionmentioning

confidence: 99%

Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Saydam

2021

Front. Cell Dev. Biol.

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“…These differences, which define the concept of clonality in tumours, are a potentially detrimental hallmark of cancer. In particular, tumour sub-populations may possess a unique combination of molecular traits that enables them to evade treatment [18, 7, 10, 20, 57, 18, 38]. The heterogeneous environment arising from such sub-populations has been mainly investigated through bulk measurements [36, 14, 68].…”

Section: Introductionmentioning

confidence: 99%

Assessing heterogeneity in spatial data using the HTA index with applications to spatial transcriptomics and imaging

Levy-Jurgenson

Tekpli

Yakhini

2021

Preprint

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Tumour heterogeneity is being increasingly recognised as an important characteristic of cancer and as a determinant of prognosis and treatment outcome. Emerging spatial transcriptomics data hold the potential to further our understanding of tumour heterogeneity and its implications. However, existing statistical tools are not sufficiently powerful to capture heterogeneity in the complex setting of spatial molecular biology. We provide a statistical solution, the HeTerogeneity Average index (HTA), specifically designed to handle the multivariate nature of spatial transcriptomics. We prove that HTA has an approximately normal distribution, therefore lending itself to efficient statistical assessment and inference. We first demonstrate that HTA accurately reflects the level of heterogeneity in simulated data. We then use HTA to analyse heterogeneity in two cancer spatial transcriptomics datasets: spatial RNA sequencing by 10x Genomics and spatial transcriptomics inferred from H&E. Finally, we demonstrate that HTA also applies to 3D spatial data using brain MRI. In spatial RNA sequencing we use a known combination of molecular traits to assert that HTA aligns with the expected outcome for this combination. We also show that HTA captures immune-cell infiltration at multiple resolutions. In digital pathology we show how HTA can be used in survival analysis and demonstrate that high levels of heterogeneity may be linked to poor survival. In brain MRI we show that HTA differentiates between normal ageing, Alzheimer's disease and two tumours. HTA also extends beyond molecular biology and medical imaging, and can be applied to many domains, including GIS. Source code and python package are available at https://alonalj.github.io/HTA.html .

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“…Cells of minimal residual disease may develop through positive selection of newly mutated, resistant clones (clonal evolution hypothesis). Alternatively, they may originate from resistant cancer stem cells (CSCs), which lie at to the top of the tumor hierarchy (cancer stem cell hypothesis) [ 6 , 7 , 8 ]. These two models are not mutually exclusive and both may contribute to intratumoral heterogeneity [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy

Valcz¹,

Buzás

Sebestyén

et al. 2020

Cancers

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Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue “niche”, cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.

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Drug resistance: origins, evolution and characterization of genomic clones and the tumor ecosystem to optimize precise individualized therapy

Cited by 29 publications

References 89 publications

Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Assessing heterogeneity in spatial data using the HTA index with applications to spatial transcriptomics and imaging

Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy

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