Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma

Sato, Takashi; Yoo, Seungyeul; Kong, Ranran; Sinha, Abhilasha; Chandramani-Shivalingappa, Prashanth; Patel, Ayushi; Fridrikh, Maya; Nagano, Osamu; Masuko, Takashi; Beasley, Mary Beth; Powell, Charles A.; Zhu, Jun; Watanabe, Hideo

doi:10.1158/0008-5472.can-19-2132

Cited by 30 publications

(20 citation statements)

References 62 publications

(70 reference statements)

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“…We observed preferential accessibility at distinct genetic loci in L-Myc cell lines when compared to c-Myc cell lines (Figure 2E). This included augmented accessibility in L-Myc cell lines at lung and neuron development factor FOXA2 ( 32 , 33 ) (Figure 2E) and POU3F2 (Brn2), a neuronal lineage factor of lung squamous cancer (Figure S2D) ( 34 ); while in c-Myc cell lines at cell surface adhesion factor ITGA4 (Figure 2E) and neuronal repressor, REST (Figure S2E). Consistent with the epigenetic results, we found protein expression of Brn2 was significantly higher in L-Myc-classified cell lines, and Rest expression was highest in two c-Myc-classified cell lines with highest Myc accessibility at its locus while there was no statistically significant difference between c-Myc and L-Myc classified cell lines (Figure S2F).…”

Section: Resultsmentioning

confidence: 99%

Classic oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer

Patel

Yoo

Kong

et al. 2019

Preprint

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Comprehensive genomic analyses of small cell lung cancer (SCLC), the most aggressive form of lung cancer, have revealed near universal loss of tumor suppressors (RB1 and TP53) and frequent genomic amplification of all three MYC family members. The amplification of each Myc family member is mutually exclusive; hence it had been long suggested that they are functionally equivalent. However, their expression has more recently been associated with specific neuroendocrine markers and distinct histopathology. In this study, we explored a novel role of c-Myc and L-Myc as lineage determining factors contributing to SCLC molecular subtypes and histology. Integrated analyses of a gene regulatory network generated from mRNA expression of primary SCLC tumor and chromatin state profiling of SCLC cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein the L-Myc signature was enriched for neuronal pathways while the c-Myc signature was enriched for Notch signaling and epithelial-to-mesenchymal transition. We investigated the functional redundancy and distinction of c-Myc and L-Myc, and noted the insufficiency of L-Myc to induce lineage switch in contrast to the potential of c-Myc to induce trans-differentiation. c-Myc rewires the Myc-accessible landscape and activates neuron al repressor, Rest to mediate transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, our findings reveal a previously undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses. Patel, A et al. 4

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Section: Resultsmentioning

confidence: 99%

Classic oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer

Patel

Yoo

Kong

et al. 2019

Preprint

Self Cite

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“…In addition to the general function as a TF, there is strong evidence for its role as a pioneer factor that unwraps nucleosomal DNA to enable gene expression from areas of highly packed chromatin. Cryo-electron microscopy (cryo-EM) structure and SeEN-seq data show that the HMG domain of Sox2 binds to nucleosomal entry-exit sites [ 39 , 40 ]. Together with Oct4, Sox2 kinks the DNA ~90° away from the histone octamer, initiates chromatin opening using the binding energy, which increases the accessibility of nucleosomal DNA, and thereby facilitates subsequent transcription [ 39 , 40 ].…”

Section: Roles Of Sox Tfs In Splicingmentioning

confidence: 99%

“…Cryo-electron microscopy (cryo-EM) structure and SeEN-seq data show that the HMG domain of Sox2 binds to nucleosomal entry-exit sites [ 39 , 40 ]. Together with Oct4, Sox2 kinks the DNA ~90° away from the histone octamer, initiates chromatin opening using the binding energy, which increases the accessibility of nucleosomal DNA, and thereby facilitates subsequent transcription [ 39 , 40 ]. TFs such as Klf4, Nanog, Brn2, Pax6, and ATP-consuming chromatin remodelers such as Chd7 cooperate with Sox2 for efficient chromatin opening [ 41 , 42 , 43 , 44 ].…”

Section: Roles Of Sox Tfs In Splicingmentioning

confidence: 99%

Alternate Roles of Sox Transcription Factors beyond Transcription Initiation

Zhang

Hou

2021

IJMS

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Sox proteins are known as crucial transcription factors for many developmental processes and for a wide range of common diseases. They were believed to specifically bind and bend DNA with other transcription factors and elicit transcriptional activation or repression activities in the early stage of transcription. However, their functions are not limited to transcription initiation. It has been showed that Sox proteins are involved in the regulation of alternative splicing regulatory networks and translational control. In this review, we discuss the current knowledge on how Sox transcription factors such as Sox2, Sry, Sox6, and Sox9 allow the coordination of co-transcriptional splicing and also the mechanism of SOX4-mediated translational control in the context of RNA polymerase III.

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“…Thus, heterogeneity is the rule rather than the exception. Table 1 summarizes some of the known types of heterogeneity in solid tumors [1][2][3][4][5][6][7][8][9][10][11][12][13]. Table 1.…”

Section: Heterogeneity In the Tumor Microenvironment (Tme)mentioning

confidence: 99%

Resolving Metabolic Heterogeneity in Experimental Models of the Tumor Microenvironment from a Stable Isotope Resolved Metabolomics Perspective

et al. 2020

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The tumor microenvironment (TME) comprises complex interactions of multiple cell types that determines cell behavior and metabolism such as nutrient competition and immune suppression. We discuss the various types of heterogeneity that exist in solid tumors, and the complications this invokes for studies of TME. As human subjects and in vivo model systems are complex and difficult to manipulate, simpler 3D model systems that are compatible with flexible experimental control are necessary for studying metabolic regulation in TME. Stable Isotope Resolved Metabolomics (SIRM) is a valuable tool for tracing metabolic networks in complex systems, but at present does not directly address heterogeneous metabolism at the individual cell level. We compare the advantages and disadvantages of different model systems for SIRM experiments, with a focus on lung cancer cells, their interactions with macrophages and T cells, and their response to modulators in the immune microenvironment. We describe the experimental set up, illustrate results from 3D cultures and co-cultures of lung cancer cells with human macrophages, and outline strategies to address the heterogeneous TME.

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Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma

Abstract: Transcriptional cooperation of Sox2 with p63 or Brn2 determines cancer lineage state in lung squamous cell carcinoma.

Cited by 30 publications

References 62 publications

Classic oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer

Classic oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer

Alternate Roles of Sox Transcription Factors beyond Transcription Initiation

Resolving Metabolic Heterogeneity in Experimental Models of the Tumor Microenvironment from a Stable Isotope Resolved Metabolomics Perspective

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