Spatial biology of cancer evolution

Seferbekova, Zaira; Lomakin, Artem; Yates, Lucy R.; Gerstung, Moritz

doi:10.1038/s41576-022-00553-x

Cited by 75 publications

(57 citation statements)

References 282 publications

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“…Somatic variants of FCD are enriched in neuronal cells compared to non-neuronal cells as determined by analysis using laser capture microdissection, and dysmorphic neurons and balloon cells density in bulk tissue is an important implication in detecting somatic variants [3,9]. Spatially resolved DNA analysis, which has recently been applied to cancer tissues to detect site-specific small variants or genome-wide CNVs, allows unbiased analysis including surrounding normal cells [20,31,37], and somatic variant analysis with spatial information may provide significant information for understanding the development of FCD.…”

Section: Idmentioning

confidence: 99%

An integrated genetic analysis of epileptogenic brain malformed lesions

Fujita

Kato

Sugano

et al. 2023

acta neuropathol commun

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Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

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Section: Idmentioning

confidence: 99%

An integrated genetic analysis of epileptogenic brain malformed lesions

Fujita

Kato

Sugano

et al. 2023

acta neuropathol commun

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“…Therefore, the researchers collected a large number of samples from a multiregion of carcinoma, concomitant adenoma if present, and a distant region of the normal epithelium to integrate their spatially resolved mutiomics analysis with single gland profiling data set, and combine with computational modeling to understand the cancer cell biology and assess the functional impact of altered gene expression on the evolution of CRC, due to intratumor heterogeneity is a significant confounding factor in bulk‐tumor profiling (Figure 1). As for spatially resolved multiomics analysis, it presents a new avenue to reveal tumors and microenvironments co‐evolution, which could be used to clarify heterogeneity 5 . In detail, it contains a strategy for the spatial sampling of tumor tissue to implement a series of new spatial genomic, transcriptomic, and proteomic technologies 5 …”

Section: Figurementioning

confidence: 99%

“…As for spatially resolved multiomics analysis, it presents a new avenue to reveal tumors and microenvironments co-evolution, which could be used to clarify heterogeneity. 5 In detail, it contains a strategy for the spatial sampling of tumor tissue to implement a series of new spatial genomic, transcriptomic, and proteomic technologies. 5 Heide et al 1 first looked forward to measuring genome-epigenome co-evaluation in a quantitative manner and gained some evidence.…”

mentioning

confidence: 99%

“…5 In detail, it contains a strategy for the spatial sampling of tumor tissue to implement a series of new spatial genomic, transcriptomic, and proteomic technologies. 5 Heide et al 1 first looked forward to measuring genome-epigenome co-evaluation in a quantitative manner and gained some evidence. First of all, it was confirmed that there were recurrent cancer driver mutation events in CRC.…”

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confidence: 99%

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Impact of genome and epigenome on intratumor heterogeneity in colorectal cancer

Huang

Luo

2023

MedComm – Future Medicine

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“…These observations suggest that our theoretical models of clonal dynamics during cancer treatment may be overly simplistic, and they underscore the need for more and better data. Emerging spatial genomic, transcriptomic, and proteomic technologies ( Seferbekova et al, 2022 ) hold particular promise for inferring subclonal interactions within human tumors. Below, several sections discuss challenges and opportunities integrating mathematical models with wet lab data (How can we leverage mathematical modeling to support testing of adaptive therapy in the wet lab?)…”

Section: Introductionmentioning

confidence: 99%

A survey of open questions in adaptive therapy: Bridging mathematics and clinical translation

West

Adler

Gallaher

et al. 2023

eLife

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Adaptive therapy is a dynamic cancer treatment protocol that updates (or ‘adapts’) treatment decisions in anticipation of evolving tumor dynamics. This broad term encompasses many possible dynamic treatment protocols of patient-specific dose modulation or dose timing. Adaptive therapy maintains high levels of tumor burden to benefit from the competitive suppression of treatment-sensitive subpopulations on treatment-resistant subpopulations. This evolution-based approach to cancer treatment has been integrated into several ongoing or planned clinical trials, including treatment of metastatic castrate resistant prostate cancer, ovarian cancer, and BRAF-mutant melanoma. In the previous few decades, experimental and clinical investigation of adaptive therapy has progressed synergistically with mathematical and computational modeling. In this work, we discuss 11 open questions in cancer adaptive therapy mathematical modeling. The questions are split into three sections: (1) integrating the appropriate components into mathematical models (2) design and validation of dosing protocols, and (3) challenges and opportunities in clinical translation.

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Spatial biology of cancer evolution

Cited by 75 publications

References 282 publications

An integrated genetic analysis of epileptogenic brain malformed lesions

An integrated genetic analysis of epileptogenic brain malformed lesions

Impact of genome and epigenome on intratumor heterogeneity in colorectal cancer

A survey of open questions in adaptive therapy: Bridging mathematics and clinical translation

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