Really relevant work on how the axis AXL-ABL2-TAZ engage in an autocrine positive feedback loop to promote brain metastasis in lung adenocarcinoma. These results suggest that the combination treatment of the AXL inhibitor R428 and the ABL allosteric inhibitor asciminib could be a novel route to block disease progression in AXL-driven lung cancers.
Tensor decomposition techniques have been used extensively in many projects in our lab, such as mapping model-predicted common gamma chain cytokine responses, reasoning antigen-specific systems serology data, and improving cancer cell line drug response predictions. To understand tensor decomposition methods, this paper is a good place to start.
Very interesting approach to disentangle signaling networks using global phosphoproteomic measurements. This novel method infers kinase activity by integrating the scores of two kinase-centric components; overall kinase phosphorylation levels and activation loop phosphorylation, and two substrate-centric components; quantification of experimentally reported kinase-substrate relationships shown in PhosphoSitePlus and levels of kinase substrates predicted by an algorithm–NetworKIN–that performs motif-based predictions to pinpoint kinases responsible for specific phosphorylation events.
Last week our lab reviewed what’s sure to be a seminal systems pharmacology paper from the Quaranta lab, Meyer et al. “Quantifying Drug Combination Synergy along Potency and Efficacy Axes”, in @CellSystemsCP. Thread 👇 pic.twitter.com/bSBgBDV8eg
— Aaron Meyer (@aarmey) April 22, 2019
Six simple tips to help ensure progress during your Ph.D. studies.
Effector function allows antibodies to communicate with a large portion of the immune system. Now, it looks like anti-CTLA4 antibodies can also take advantage of this, but depleting regulatory T cells. Effector signaling is complicated and important enough there is surely much engineering still to be done.
These results are remarkable: Warfarin (an accidental TAM inhibitor) reduces incidence of cancer by ~20% in patients >50. These new results complement some of the less definitive results of earlier studies.
An interesting paper on the relationship between the development of tolerance and resistance. It’s in bacteria but surely has direct ties to selectively toxic drugs in cancer as well. They show that tolerance can directly enable rare, resistance-causing mutations to develop. They also come up with an explanation for why tolerance would develop before resistance—the routes to tolerance are by many different mutational changes, while resistance had a more restrictive set of routes.
This work shows that in addition to being a tumor cell-intrinsic resistance factor to ionizing radiation, AXL signaling drives decreased MHC-I abundance and immunosuppressive cytokine expression. The AXL-proximal signaling that drives this effect is not worked out—it would be interesting to know what signaling is involved to determine how specific this is to TAM receptors vs. other kinases.
An interesting paper from a few hospitals, mainly in Boston. They’re doing targeted capture and sequencing of a broad panel of patients to try and design therapies around that data. They find focal amplification of AXL in ~1% of patients. AXL inhibitor was tried in one of those patients and gave a striking response.
A really interesting study on how IGF1 acts as a signal from macrophages to redirect efferocytosis toward immune cells. The redirection works even with phosphatidylserine vesicles, and prevents inflammation after an allergy challenge.
Cummings et al created an experimental model in which they could selectively induce apoptosis in a subpopulation of cells, which then allowed them to look at the response within the surrounding cells. Apoptotic cell debris leads to an immunosuppressive response in a variety of cell types, though with important differences as well.
Practical advice for how to best present scientific data. As stated in the article, “a more accurate definition for scientific visualization would be a graphical interface between people and data.”
We frequently are asked about the use of warfarin in cancer patients and whether it is linked to survival. This is a list of a few studies found in the literature.
A study that investigates the dynamics of phenotypic proportions in human breast cancer cell lines. They observe that subpopulations of purified phenotype return to their equilibrium and they find transition probabilities of this stochastic behavior by a Markov model. Their findings contribute to our understanding of cancer heterogeneity and reveal how stochasticity in single-cell behaviors promotes phenotypic equilibrium in populations of cancer cells.
This paper is an exemplary study of phenotypic heterogeneity in drug response as a source of resistance. They observe that individual PC9 lung cancer cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potential lethal exposures.
A first, classic model of Fc receptor activation.
Our lab has developed a multi-ligand, multi-receptor, multi-valent binding model. It has been utilized to model the antibody Fc-FcγR interactions as well as to improve drug selective cell population binding. This classical biophysics work is the original wisdom that inspires our model.