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Reposted by Gianna T. Busch

Alfonso Martinez Arias @amartinezarias.bsky.social · 15/07/2025

Two new preprints from the @arjunraj.bsky.social‬ on #gastruloids. Both excellent. Exploring the relationship between macroscopic reproducibility v microscopic heterogeneity. Stunning experiments and much to think about biorxiv.org/content/earl... biorxiv.org/content/earl...

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Reposted by Gianna T. Busch

Arjun Raj @arjunraj.bsky.social · 03/06/2025

NimbusImage is great for spot analysis using the Piscis model from Will Niu; give it a try! www.nimbusimage.com www.loom.com/share/49d795...

nimbusimage.com

NimbusImage

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

Thank you to @arjunraj.bsky.social for his thoughtful mentorship, as well as my co-authors and labmates for their support! (11/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

By considering population heterogeneity, we uncover therapeutic opportunities invisible in bulk assays and expand the pool of viable drugs. This approach provides a framework for developing more effective strategies to overcome therapy resistance in melanoma and potentially other cancers. (10/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

Finally, we see that some drugs appear to target sensitivities in the population of drug-naive cells that are “primed” to become resistant, and these sensitivities can be lost as the cells become fully resistant. (9/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

Through a collaboration with Stephanie Huang and Robert Gruener at the University of Minnesota, we showed that their independent drug action-based model, IDACombo, could accurately predict combination efficacy. (8/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

When we tested this combination in vitro, we saw that it was indeed more effective than either drug individually! This result is an example of population-based synergy, where two drugs target distinct populations, rather than both drugs acting on the same population. (7/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

We wondered whether there were combinations of drugs targeting distinct subsets of the resistant clones. To test this, we expanded our pool of clones and identified a number of potential combinations, including the example shown. (6/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

To test this, we generated clonal, resistant cell lines (dubbed resistant clones) from individual resistant colonies and screened them with a pan-cancer drug library. We found that resistant clones indeed had distinct drug sensitivities! (5/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

If so, there may not actually be one “silver bullet” that could kill all the cells. Instead, drugs may target distinct subpopulations of resistant cells. In a bulk assay, such drugs might appear to have similar partial effects, but could actually be quite effective in combination. (4/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

We have shown resistant cells exhibit morphological and transcriptional variation, even among a clonal population (Goyal et al. 2023). We also see this transcriptional variation in patients (Boe et al. 2024). However, we did not know whether these cells also had distinct drug sensitivities. (3/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

Targeted therapy resistance remains a significant clinical problem. So why has it been so difficult to kill these cells? One potential explanation is the emerging realization that the resistant population is not homogeneous, but rather is composed of many different subpopulations. (2/10)

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Gianna T. Busch @giannatbusch.bsky.social · 28/04/2025

(Quick plug for #AACR25, if you like what you see below I am giving a talk on Tuesday 4/29 at 3:35pm in Room E450B in the Lakeside Center during the Experimental Therapeutics: Drug Resistance minisymposium!)

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