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On November 23rd 2021, Tincy defended her thesis “An Integrative Genetic, and Epigenetic Characterization of Pancreatic Neuroendocrine Neoplasms (PanNENs) defines Distinct Molecular Features of Endocrine- and Exocrine-like Subgroups”.

In her work, Tincy analyzed how two sub-entities of PanNENs – so called PanNETs and PanNECs, differ in their DNA methylation patterns and other molecular features. This is important, as high-grade PanNETs are often hard to distinguish from PanNECs by classical morphological analyses used in pathology, yet have a different prognosis and response to specific therapies. Further, Tincy’s work addresses the cell-of-origin of either entity.

The upcoming CompCancer Seminar will be hosted by Stefan Peidli. Find the invitation below. The link is available from compcancer at charite dot de.

Dear all,

I'm excited to announce next weeks CompCancer Literature Seminar (Wednesday 15.09.) with Louis Cammarata and Adit Radhakrishnan from the lab of Caroline Uhler. 

Due to different time zones, the seminar will be at 5pm instead of 10am.

Louis and Adit will introduce us to overparametrized autoencoders and present their latest work where they developed a causal drug repurposing pipeline. This pipeline first identifies relevant drug responses in the latent space of an overparametrized autoencoder fed with drug perturbation data from e.g. CMap. In the paper, they applied their pipeline for drug repurposing against COVID-19.

Best,

Stefan

Maintaining and escaping feedback control in hierarchically organised tissue: a case study of the intestinal epithelium

Matthias M. Fischer, Hanspeter Herzel, and Nil Blüthgen

doi: https://doi.org/10.1101/2021.06.11.448040

Abstract

The intestinal epithelium is one of the fastest renewing tissues in mammals with an average turnover time of only a few days. It shows a remarkable degree of stability towards external perturbations such as physical injuries or radiation damage. Tissue renewal is driven by intestinal stem cells, and differentiated cells can de-differentiate if the stem cell niche is lost after tissue damage. However, self-renewal and regeneration require a tightly regulated balance to uphold tissue homoeostasis, and failure can lead to tissue extinction or to unbounded growth and cancerous lesions. Here, we present a mathematical model of intestinal epithelium population dynamics that is based on the current mechanistic understanding of the underlying biological processes. We derive conditions for stability and thereby identify mechanisms that may lead to loss of homoeostasis. A key results is the existence of specific thresholds in feedbacks after which unbounded growth occurs, and a subsequent convergence of the system to a stable ratio of stem to non-stem cells. A biologically interesting property of the model is that the number of differentiated cells at the steady-state can become invariant to changes in their apoptosis rate. Moreover, we compare alternative mechanisms for homeostasis with respect to their recovery dynamics after perturbation from steady-state. Finally, we show that de-differentiation enables the system to recover more gracefully after certain external perturbations, which however makes the system more prone to loosing homoeostasis.

https://www.biorxiv.org/content/10.1101/2021.06.11.448040v1

The upcoming CompCancer Seminar will be hosted by Bettina Schmidt. Find the invitation below. The link is available from compcancer at charite dot de.

Dear PI's and fellow students,

in our next CompCancer seminar on Wednesday, 2nd of June at 10 AM, please welcome Bernd Bodenmiller, who will talk about his newly published paper (19.5.21, Cell Systems) https://www.sciencedirect.com/science/article/pii/S2405471221001113 on drug-sensitivity prediction based on signaling pathways in breast cancer.

It is interesting for you if you work on

#signaling pathways  #CyTOF  #drug-sensitivity prediction #bigdata #MANOVA #precision medicine

and I'm sure many different things that I did not capture. Feel free to forward this information to people who could be interested

Summary

One goal of precision medicine is to tailor effective treatments to patients’ specific molecular markers of disease. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data—on more than 80 million single cells from 4,000 conditions—were used to fit mechanistic signaling network models that provide insight into how cancer cells process information. Our dynamic single-cell-based models accurately predicted drug sensitivity and identified genomic features associated with drug sensitivity, including a missense mutation in DDIT3 predictive of PI3K-inhibition sensitivity. We observed similar trends in genotype-drug sensitivity associations in patient-derived xenograft mouse models. This work provides proof of principle that patient-specific single-cell measurements and modeling could inform effective precision medicine strategies.

See you then,

Bettina

We would like to announce our upcoming Life after PhD (LAP) seminar, which will take place on Tuesday, 11.5.2021 at 4:30 pm on Zoom (the link is available from compcancer at charite dot de).

Our guest will be Dr. Bastian Gastl, who will share insights into his career path and current occupation as a Medical Science Liaison at Novocure. After having worked at a bank for a short time, he decided to switch gears entirely and did his Bachelor’s degree in Biology at the Ludwigs-Maximilians Universität in Munich. Following up on this, Bastian pursued his Master’s degree at Charité in Molecular Medicine. He extended his stay at Charité by doing his PhD in the group for Molecular Tumorpathology, focusing on effects of reduced DNA replication efficiency in KRAS-mutatant colorectal cancer cell models. When looking for interesting positions outside of academia after finishing his PhD, he first took up work as a Digital Business Consultant, before changing for his current job at Novocure.

Join us to find out about Bastian’s experiences on this way and get tips and hints for perspectives after completing your PhD!

Best wishes,

Wiebke (IRTG2403), Juliane (IRTG2290), and Pamela (CompCancer/ RTG2424)

For more information about this series, visit the IRTG 2403 website: https://www.regulatory-genome.hu-berlin.de/en/events/lectures/lap-series