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Huge Congratulations Allan!!

Lastly, a big thank you to my fabulous wife Ivel and our 2 boys for unending support and keeping me grounded. And for an additional year on the tenure clock;)

Also big thanks to former advisors David Schaffer and Wendell Lim for continued mentorship and for showing me how to do this job well.

Penn BE has been a fantastic place to launch a lab, with maximally supportive leadership(Chairs Dave Meaney and Ravi Radhakrishnan, and Dean Kumar, and world-class colleagues who doubled as close mentors, esp. Arjun Raj, Ken Zaret, Lewis Chodosh.

Highlights: Keynotes: Tobias Meyer and Jin Zhang Sessions on metabolism, development, stress, immune, cell cycle, optogenetics, image analysis Workshops on advanced microscopy, organoids Meet-the-experts: academia, industry, publishing Networking (+line dancing!) in Nashville Early reg. ends 5/10!

Thanks Olivier! If you mean recruiting proteins to subcellular compartments--yes. If you mean rearranging organelles within the cell, we thought about it but have not tried it out.

See also a concurrent preprint showing that diverse RTK fusions can suppress transmembrane EGFR. These other fusions also mostly did *not* form condensates, but did form small, active multimers. www.biorxiv.org/content/10.1...

EGFR suppression and drug-induced potentiation are widespread features of oncogenic RTK fusionsRegulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell’s perception of its environment is not c...www.biorxiv.org

Summary: small fusion multimers are sufficient (tho not necessary!) to drive signaling and tumors. While condensates can form, they appear incidental. But if not condensates, then how do fusions signal from the cytoplasm? More to come here!

5) Finally, a panel of other oncogenic RTK fusions shows that only few form condensates, and none show correlation between condensation and signaling at single-cell.

4) Unexpectedly, even cytoplasmic *monomers* (const. active) can drive signaling and tumor formation, despite complete lack of multimerization that is essential for condensation.

3) If condensates are dispensable, diffuse (non-condensing) ALK fusions should be able to signal and drive tumor growth. Indeed they can! Synthetic, cytoplasmic ALK dimers don’t condense but do signal, and also form tumors in mice.

2) There is lots of active oncogene (pALK) in the diffuse phase, and when treated with ALK inhibitor, timescale of decay in the diffuse phase matches that of downstream signals, but decay in condensates is much slower.

Evidence of dispensability? 1) EML4-ALK condensation is biphasic (highest at mid levels), but signaling increases monotonically w expression. Thus the strongest signaling is in cells with *no* condensates.

The condensate (large foci) model suggests that condensates of fusions (e.g. EML4-ALK) are an essential organizer of signaling in the cyto, in the absence of membrane. Causality is unclear though because perturb's of condensates are often also perturb's of kinase activity.

tagging first author @carolgyz.bsky.social. Congratulations Carol!!

In sum, RTK fusions are simultaneously activators AND suppressors of mitogenic signaling. We expect future studies can exploit this suppressive behavior for biomimetic therapies designed to enhance killing & combat drug tolerance.

Finally, synthetic optogenetic RTK fusions demonstrated the key principles: 1) Grb2 binding and sequestration could be decoupled from fusion signaling, and 2) Grb2 sequestration in the cyto is sufficient to desensitize cells to EGFR stim (without signaling).

Targeted therapy (kinase inhibitors) releases Grb2 and relieves suppression. Potential therapeutic importance because drugs permit receptor signaling that promotes tolerance.

Mechanism? Fusions sequester adapters like Grb2 in cyto and prevent translocation to active EGFR at membrane. Previously shown for EML4-ALK, below for TPM3-ROS, same for (almost) all fusions tested

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Main surprise: condensates (large foci) are *not* important for EGFR suppression. For EML4-ALK, condensates co-occur with suppression, but for most fusions -- no condensates. See concurrent preprint for more surprises on the role of condensates in fusions. www.biorxiv.org/content/10.6...