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Open AccessArticle

A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer

1
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
2
Philips Molecular Pathway Dx, Royal Philips, 5656 AE Eindhoven, The Netherlands
3
Philips Research, Royal Philips, 5656 AE Eindhoven, The Netherlands
*
Author to whom correspondence should be addressed.
These authors share equal contribution.
Present address: Department of Immunology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands.
§
These authors share equal senior authorship.
Cancers 2020, 12(11), 3142; https://doi.org/10.3390/cancers12113142
Received: 24 September 2020 / Revised: 16 October 2020 / Accepted: 18 October 2020 / Published: 27 October 2020
(This article belongs to the Section Methods and Technologies Development)
The Notch signal transduction pathway is important for various physiological processes, including immune responses, and plays a role in many diseases, for example cancer. We have developed a new assay to quantitatively measure Notch pathway activity, and we validated it using data from various human cancer cell lines. The assay can be applied across different cell types, and offers numerous possibilities to explore the contribution of the Notch pathway to tumor formation and the stratification of cancer patients. We assessed Notch pathway activity in a cohort of T cell acute lymphoblastic leukemia (T-ALL) patient samples, and found that the pathway activity score more accurately reflects Notch pathway activity than a prediction on the basis of NOTCH1 mutations alone. Finally, we found that patients with low Notch pathway activity had a significantly shorter event-free survival compared to patients who had T-ALL cells with higher activity.
Background: The Notch signal transduction pathway is pivotal for various physiological processes, including immune responses, and has been implicated in the pathogenesis of many diseases. The effectiveness of various targeted Notch pathway inhibitors may vary due to variabilities in Notch pathway activity among individual patients. The quantitative measurement of Notch pathway activity is therefore essential to identify patients who could benefit from targeted treatment. Methods: We here describe a new assay that infers a quantitative Notch pathway activity score from the mRNA levels of generally conserved direct NOTCH target genes. Following the calibration and biological validation of our Notch pathway activity model over a wide spectrum of human cancer types, we assessed Notch pathway activity in a cohort of T-ALL patient samples and related it to biological and clinical parameters, including outcome. Results: We developed an assay using 18 select direct target genes and high-grade serous ovarian cancer for calibration. For validation, seven independent human datasets (mostly cancer series) were used to quantify Notch activity in agreement with expectations. For T-ALL, the median Notch pathway activity was highest for samples with strong NOTCH1-activating mutations, and T-ALL patients of the TLX subtype generally had the highest levels of Notch pathway activity. We observed a significant relationship between ICN1 levels and the absence/presence of NOTCH1-activating mutations with Notch pathway activity scores. Patients with the lowest Notch activity scores had the shortest event-free survival compared to other patients. Conclusions: High Notch pathway activity was not limited to T-ALL samples harboring strong NOTCH1 mutations, including juxtamembrane domain mutations or hetero-dimerization combined with PEST-domain or FBXW7 mutations, indicating that additional mechanisms may activate Notch signaling. The measured Notch pathway activity was related to intracellular NOTCH levels, indicating that the pathway activity score more accurately reflects Notch pathway activity than when it is predicted on the basis of NOTCH1 mutations. Importantly, patients with low Notch pathway activity had a significantly shorter event-free survival compared to patients showing higher activity. View Full-Text
Keywords: Notch pathway activity; NOTCH1 mutation; T cell acute lymphoblastic leukemia Notch pathway activity; NOTCH1 mutation; T cell acute lymphoblastic leukemia
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MDPI and ACS Style

Canté-Barrett, K.; Holtzer, L.; van Ooijen, H.; Hagelaar, R.; Cordo’, V.; Verhaegh, W.; van de Stolpe, A.; Meijerink, J.P.P. A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer. Cancers 2020, 12, 3142. https://doi.org/10.3390/cancers12113142

AMA Style

Canté-Barrett K, Holtzer L, van Ooijen H, Hagelaar R, Cordo’ V, Verhaegh W, van de Stolpe A, Meijerink JPP. A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer. Cancers. 2020; 12(11):3142. https://doi.org/10.3390/cancers12113142

Chicago/Turabian Style

Canté-Barrett, Kirsten; Holtzer, Laurent; van Ooijen, Henk; Hagelaar, Rico; Cordo’, Valentina; Verhaegh, Wim; van de Stolpe, Anja; Meijerink, Jules P.P. 2020. "A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer" Cancers 12, no. 11: 3142. https://doi.org/10.3390/cancers12113142

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