Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer

Li, Yong; He, Yi; Peng, Junya; Su, Zhendong; Li, Zeyao; Zhang, Bingjie; Ma, Jing; Zhuo, Meilian; Zou, Di; Xin-de, Liu; Liu, Xinhong; Wang, Wenze; Huang, Dan; Xu, Mingang; Wang, Jianbin; Deng, Haiteng; Xue, Jing; Xie, Wei; Lan, Xun; Chen, Mo; Zhao, Yupei; Wu, Wenming; David, Charles J.

doi:10.1038/s43018-020-00134-z

Cited by 66 publications

(68 citation statements)

References 58 publications

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“…We recapitulated this shift from a classical to a more IT state in organoid models exposed to IFNγ, suggesting that malignant adaptation to signals from the TME may contribute to driving IT and basal phenotypes. Similar to the relationship between inflammation and tumorigenesis (Alonso-Curbelo et al, 2021;Li et al, 2021), we speculate that as tumors become inflamed and immune-activated, malignant cells display enhanced plasticity, transition to an IT state in response, and then progress to a fully basal phenotype with concomitant immune evasion and exclusion. These relationships may have implications for PDAC response to immunotherapy given that a productive immune response may promote more aggressive basal phenotypes (Benci et al, 2016;Li et al, 2018).…”

Section: Discussionsupporting

confidence: 79%

“…This finding suggests that while upregulation of KRAS signaling by amplification or other mechanisms may play an important role in the transition toward the basal state (Chan-Seng-Yue et al, 2020;Miyabayashi et al, 2020), it may become less functionally important once this state transition is complete. Furthermore, the presence of IT cells enriched for KRAS and inflammatory response gene expression is reminiscent of phenotypes seen in mouse models that suggest inflamed progenitor-like cells as those that tolerate KRAS mutations and initiate tumorigenesis (Alonso-Curbelo et al, 2021;Li et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

Raghavan

Winter

Navia

et al. 2020

Preprint

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In pancreatic ductal adenocarcinoma (PDAC), the basal-like and classical transcriptional subtypes are associated with differential chemotherapy sensitivity and patient survival. These phenotypes have been defined using bulk transcriptional profiling, which can mask underlying cellular heterogeneity and the biologic mechanisms that distinguish these subtypes. Furthermore, few studies have interrogated metastases, which are the cause of mortality in most patients with this highly lethal disease. Using single-cell RNA-sequencing of metastatic needle biopsies and matched organoid models, we demonstrate intra-tumoral subtype heterogeneity at the single-cell level and define a continuum for the basal-like and classical phenotypes that includes hybrid cells that co-express features of both states. Basal-like tumors show enrichment of mesenchymal and stem-like programs, and demonstrate immune exclusion and tumor cell crosstalk with specific macrophage subsets. Conversely, classical tumors harbor greater immune infiltration and a relatively pro-angiogenic microenvironment. Matched organoid models exhibit a strong bias against the growth of basal-like cells in standard organoid media, but modification of culture conditions can rescue the basal-like phenotype. This study reframes the transcriptional taxonomy of PDAC, demonstrates how divergent transcriptional subtypes associate with unique tumor microenvironments, and highlights the importance of evaluating both genotype and transcriptional phenotype to establish high-fidelity patient-derived cancer models.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

Raghavan

Winter

Navia

et al. 2020

Preprint

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“…These processes also lead to enduring lineage infidelities and the commissioning of tumor related super-enhancers (Ge et al, 2017). Furthermore, Li et al show that pancreatic inflammation is linked to a transient metaplastic progenitor cell population harboring a proto-oncogene mediated enhancer network that is coopted by mutant Kras to subsequently drive tumorigenesis, suggesting that inflammation can also promote oncogenesis by gene enhancer network remodeling (Li et al, 2021). Moreover, innate immune priming and associated immune modulatory states can occur as a result of deregulation of specific immune molecular effector stress response pathways and result in a spectrum of context-specific outcomes including multiple forms of programmed cell death such as apoptosis, necroptosis, pyroptosis, inflammatory states, autoimmunity as well as immune deficiency with profound implications for intermediate and more long-term COVID-19 sequelae (Li et al, 2019;Lalaoui et al, 2020;Malireddi et al, 2020).…”

Section: Systemic Viral Sequelaementioning

confidence: 99%

Nervous System-Systemic Crosstalk in SARS-CoV-2/COVID-19: A Unique Dyshomeostasis Syndrome

et al. 2021

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SARS-CoV-2 infection is associated with a spectrum of acute neurological syndromes. A subset of these syndromes promotes higher in-hospital mortality than is predicted by traditional parameters defining critical care illness. This suggests that deregulation of components of the central and peripheral nervous systems compromises the interplay with systemic cellular, tissue and organ interfaces to mediate numerous atypical manifestations of COVID-19 through impairments in organismal homeostasis. This unique dyshomeostasis syndrome involves components of the ACE-2/1 lifecycles, renin-angiotensin system regulatory axes, integrated nervous system functional interactions and brain regions differentially sculpted by accelerated evolutionary processes and more primordial homeostatic functions. These biological contingencies suggest a mechanistic blueprint to define long-term neurological sequelae and systemic manifestations such as premature aging phenotypes, including organ fibrosis, tissue degeneration and cancer. Therapeutic initiatives must therefore encompass innovative combinatorial agents, including repurposing FDA-approved drugs targeting components of the autonomic nervous system and recently identified products of SARS-CoV-2-host interactions.

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“…Since enhancers (and super-enhancers) function through DNA binding motifs, their activity is vulnerable to variation that modulates the binding capacity of transcription factor proteins, thus altering transcription of the target gene [128]. Presence of CNA (and other architectural disarrangements) combined with loss of insulation events can lead to ectopic enhancer creation or activity resulting into metaplastic differentiation associated with malignancy (Figure 2C, [129][130][131]). For example, genome-wide CNA studies have correlated a deletion in an ovarian-specific enhancer with altered expression of EGLN2, an enzyme that mediates hydroxylation and subsequent degradation of the HIF1A protein (a master regulator of oxygen homeostasis) in normoxia (Figure 2C, [75]).…”

Section: Genetic Variability In Enhancersmentioning

confidence: 99%

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

Lange

Begolli

Giakountis

2021

ncRNA

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The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

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Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer

Cited by 66 publications

References 58 publications

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

Nervous System-Systemic Crosstalk in SARS-CoV-2/COVID-19: A Unique Dyshomeostasis Syndrome

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

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