Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells

Goyal, Yogesh; Busch, Gianna T.; Pillai, Maalavika; Li, Jingxin; Boe, Ryan H.; Grody, Emanuelle I.; Chelvanambi, Manoj; Dardani, Ian; Emert, Benjamin; Bodkin, Nicholas; Braun, J. J.; Fingerman, Dylan; Kaur, Amanpreet; Jain, Neil; Ravindran, Pavithran; Mellis, Ian A.; Kiani, Karun; Alicea, Gretchen M.; Fane, Mitchell; Ahmed, Saifuddin; Li, Haiyin; Chen, Yeqing; Chai, Cedric; Kaster, Jessica; Witt, Russell G.; Lazcano, Rossana; Ingram, Davis R.; Johnson, Sarah; Wani, Khalida; Dunagin, Margaret C.; Lazar, Alexander J.; Weeraratna, Ashani T.; Wargo, Jennifer A.; Herlyn, Meenhard; Raj, Arjun

doi:10.1038/s41586-023-06342-8

Cited by 69 publications

(92 citation statements)

References 67 publications

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“…The data show that TRIM28 haploinsufficiency generates two reproducible developmental morphs at the organismal level and that these differ in their cancer susceptibility; one “resistant”, and one more “susceptible”. Conceptually, the result is similar to epigenetic heterogeneity described within tumors 63 and between tumors 64,65 , except at the inter-organismal level. How meta-stable states between identical cells or organisms are imposed remains unclear, though pioneering work on meta-stability of variegating reporters implicate epigenetic silencing machinery 66–70 .…”

Section: Discussionsupporting

confidence: 76%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility ′states′ in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

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Section: Discussionsupporting

confidence: 76%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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“…Besides drug resistance, the mutations that boost drug tolerance could also be sampled in the large mutation pool of tumor cells, A recent study by Razavi et al has shown that at least tens of genes have been identified to be capable of endocrine therapy tolerance 24 , therefore we can expect that the number of mutations that grant drug tolerance will be over one hundred ( Supplementary Note 2 ). Due to the neutral evolution and the diverse pool of mutations existing in tumors as well as cultured cells (even in single-cell expanded clones 43 ), we would expect that the cells with various degrees of drug tolerance have already emerged from neutral evolution.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells

Niu,

Zhang,

Luo

et al. 2023

Preprint

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Accurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution.

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“…Bulk paired‐end (61:8:8:61) RNA sequencing was done using MiRNeasy Micro Kit (Qiagen 217,084) for extraction, NEBNext® Poly(A) mRNA Magnetic Isolation Module (E7490L), NEBNext® Ultra™ II RNA Library Prep Kit for Illumina® (E7770L), and NEBNext® Multiplex Oligos for Illumina® (Dual Index Primers Set 1) (E7600S), as described previously 43,44 . Prior to library preparation, the samples were randomized to avoid experimental and human biases.…”

Section: Methodsmentioning

confidence: 99%

“…Oligos for Illumina ® (Dual Index Primers Set 1) (E7600S), as described previously. 43,44 Prior to library preparation, the samples were randomized to avoid experimental and human biases. We started our experiments with a total of 24 samples (iPSCs and differentiated iPSCs-ECs) from healthy and disease patients.…”

Section: Flow Cytometrymentioning

confidence: 99%

Modeling diabetic endothelial dysfunction with patient‐specific induced pluripotent stem cells

Gorashi,

Rivera‐Bolanos,

Dang

et al. 2023

Bioengineering & Transla Med

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Diabetes is a known risk factor for various cardiovascular complications, mediated by endothelial dysfunction. Despite the high prevalence of this metabolic disorder, there is a lack of in vitro models that recapitulate the complexity of genetic and environmental factors associated with diabetic endothelial dysfunction. Here, we utilized human induced pluripotent stem cell (iPSC)‐derived endothelial cells (ECs) to develop in vitro models of diabetic endothelial dysfunction. We found that the diabetic phenotype was recapitulated in diabetic patient‐derived iPSC‐ECs, even in the absence of a diabetogenic environment. Subsequent exposure to culture conditions that mimic the diabetic clinical chemistry induced a diabetic phenotype in healthy iPSC‐ECs but did not affect the already dysfunctional diabetic iPSC‐ECs. RNA‐seq analysis revealed extensive transcriptome‐wide differences between cells derived from healthy individuals and diabetic patients. The in vitro disease models were used as a screening platform which identified angiotensin receptor blockers (ARBs) that improved endothelial function in vitro for each patient. In summary, we present in vitro models of diabetic endothelial dysfunction using iPSC technology, taking into account the complexity of genetic and environmental factors in the metabolic disorder. Our study provides novel insights into the pathophysiology of diabetic endothelial dysfunction and highlights the potential of iPSC‐based models for drug discovery and personalized medicine.

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Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells

Cited by 69 publications

References 67 publications

Developmental priming of cancer susceptibility

Developmental priming of cancer susceptibility

Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells

Modeling diabetic endothelial dysfunction with patient‐specific induced pluripotent stem cells

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