Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium

Brandt, Raphael; Sell, Thomas; Lüthen, Mareen; Uhlitz, Florian; Klinger, Bertram; Riemer, Pamela; Giesecke‐Thiel, Claudia; Schulze, Silvia; El-Shimy, Ismail Amr; Kunkel, Désirée; Fauler, Beatrix; Mielke, Thorsten; Mages, Norbert; Herrmann, Bernhard G.; Sers, Christine; Blüthgen, Nils; Morkel, Markus

doi:10.1038/s41467-019-10954-y

Cited by 83 publications

(77 citation statements)

References 70 publications

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“…However, recent studies have shown metastasis and stemness can be uncoupled in colorectal cancer metastasis 53 , and that oncogenic mutations and paracrine signals can reverse developmental trajectories so that more differentiated cells can regain stem cell characteristics [54][55][56] . Here, we show that a gradient of ERK target gene expression is associated with developmental latent time in CRC organoids, extending our previous finding of graded ERK activity in CRC organoids 57 . The results imply a capacity for intrinsic regulation of CRC cell lifetimes via MAPK.…”

Section: Mapk Target Gene Expression Defines Crc Differentiation Statessupporting

confidence: 89%

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

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In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue. To define differences in cellular composition between the normal colon and colorectal cancer, and to map potential cellular interactions between tumor cells and their microenvironment, we profiled transcriptomes of >50,000 single cells from tumors and matched normal tissues of eight colorectal cancer patients. We find that tumor formation is accompanied by changes in epithelial, immune and stromal cell compartments in all patients. In the epithelium, we identify a continuum of five tumor-specific stem cell and progenitor-like populations, and persistent multilineage differentiation. We find multiple stromal and immune cell types to be consistently expanded in tumor compared to the normal colon, including cancer-associated fibroblasts, pericytes, monocytes, macrophages and a subset of T cells. We identify epithelial tumor cells and cancer-associated fibroblasts as relevant for assigning colorectal cancer consensus molecular subtypes. Our survey of growth factors in the tumor microenvironment identifies cell types responsible for increased paracrine EGFR, MET and TGF-β signaling in tumor tissue compared to the normal colon.We show that matched colorectal cancer organoids retain cell type heterogeneity, allowing to define a distinct differentiation trajectory encompassing stem and progenitor-like tumor cells. In summary, our single-cell analyses provide insights into cell types and signals shaping colorectal cancer cell plasticity.

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Section: Mapk Target Gene Expression Defines Crc Differentiation Statessupporting

confidence: 89%

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

Self Cite

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“…These data contrast with observations that ectopic expression of RAS mutants does drive strong over-activation of ERK, as would be expected from simple amplification by RAF/MEK/ERK (Konishi et al, 2007;Park et al, 2006). These contradictory observations could arise for various reasons, including feedback in the RAS/ERK pathway (Courtois-Cox et al, 2006), oncogene-induced senescence (Sarkisian et al, 2007), additional mutations, or tissue-or cell type-specific effects (Brandt et al, 2019). However, these possibilities cannot be disentangled without first addressing a major technical limitation inherent in the immunoblots and kinase assays that have been used almost exclusively to date.…”

Section: Introductioncontrasting

confidence: 58%

Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway

Gillies

Pargett

Silva

et al. 2020

Preprint

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Activating mutations in RAS are present in ~30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo.Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live-cell imaging in cell lines expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway-level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity independent of expression level, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the initial signaling changes induced by RAS mutations in oncogenesis are subtle.

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“…Several alterations in signalling pathway activity were also common across conditions. TGFB1 treatment and spheroids were associated with higher levels of ERK activity, which have both been linked to stemness in epithelial 34 and carcinoma cells 35 . In EGF-free media, paracrine/autocrine signalling is established, maintaining ERK activity in stem cell populations of intestinal organoids 35 .…”

Section: Brca1 Loss Promotes Emt-independent Stemness In Mosementioning

confidence: 97%

“…TGFB1 treatment and spheroids were associated with higher levels of ERK activity, which have both been linked to stemness in epithelial 34 and carcinoma cells 35 . In EGF-free media, paracrine/autocrine signalling is established, maintaining ERK activity in stem cell populations of intestinal organoids 35 . While these mechanisms may contribute to stemness in OSE spheroids or those treated with TGFB1, increased ERK activity was not enhanced following Snail overexpression or Brca1 loss.…”

Section: Brca1 Loss Promotes Emt-independent Stemness In Mosementioning

confidence: 97%

Transcriptional heterogeneity of stemness phenotypes in the ovarian epithelium

Carter

Cook

McCloskey

et al. 2020

Preprint

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The ovarian surface epithelium (OSE) is a monolayer of epithelial cells covering the surface of the ovary. During ovulation, the OSE is ruptured to allow release of the oocyte. This wound is quickly repaired, but mechanisms of this repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial tissues is widely accepted, such as the intestinal epithelium, airway epithelium, and skin, but their involvement in OSE maintenance is unclear. While putative stem cell populations in the OSE have been described, how they are regulated is poorly defined. We show that traits associated with stem cells (stemness) can be increased in OSE following exposure to the cytokine TGFB1, overexpression of the transcription factor Snai1 , or deletion of Brca1 . By assessing the gene expression profiles of these populations, we show that stemness is often linked to mesenchymal-associated gene expression and higher activation of ERK signalling, but it is not consistently dependent on their activation. Expression profiles of these populations are extremely context specific, suggesting that stemness may not correspond to a single, distinct population, but rather is a heterogenous state that can possibly emerge from diverse environmental cues. Together, these findings support that the OSE may not require distinct stem cell populations for long-term maintenance, and may achieve this through transient dedifferentiation into a stem-like state./

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Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium

Cited by 83 publications

References 70 publications

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway

Transcriptional heterogeneity of stemness phenotypes in the ovarian epithelium

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