Thanks Ronja!! Sorry I missed your message! 🫣🫣

Thanks Mathieu. Indeed, in free growth conditions stem cells also appear at the center (as in /3). It just takes longer to reach such levels of compression.

Thanks, Raimon! Yes, first... "tweet"? How do you call it here?

Gràcies, Ricard!!

Thank you!!! 😊😊

A special mention to Jochen Guck. My deepest condolences to his group and loved ones. This is just one more example of his generosity and immense contributions to science.🌹

10/ This was a huge collaborative work hand in hand with
@davidbrueckner.bsky.social , together with @vignjeviclab.bsky.social, @ehannezo.bsky.social .bsky.social , Julie Guillermet's lab, Jochen Guck's lab, @vanrheenenlab.bsky.social and Martijn's Gloerich lab. Thank you everybody!!! 🙏🙏🙏🙏

9/ Conclusion: Tumors follow reproducible self-organization programs that are sufficient to pattern cell states in time and space.
We propose that such tissue-intrinsic programs cooperate with microenvironmental cues to collectively drive phenotypic heterogeneity and plasticity.

8/ scRNA sequencing, imaging and theory showed that large organoid monolayers exhibit a biosynthetic arrest at the center, followed by a loss of stemness and death (A pattern observed in vivo by
@batllelab.bsky.social
linkinghub.elsevier.com/retrieve/pii... )

7/ Surprisingly, hierarchy also emerges in vitro above a critical size defined by the intrinsic characteristic length of the stem cell compartment.
Below critical size ➡️ homogeneous proliferation
Above critical size ➡️ hierarchy

6/ But tumor patterning is more complex than just stem- and fetal-like states...

Above a critical tumor size, proliferation and death become spatially compartmentalized: cells divide at the edge and die at the core — a pattern typically attributed to hypoxia.

5/ Indeed!
Stress measurements (in vivo & in vitro) show a correlation between compression and Lgr5. With
Jochen's Guck Lab
.
To test causality, we physically confined organoids and tumors — and confinement alone was sufficient to boost stemness! With
Julie Guillermet Lab

4/ The interplay between proliferation and expansion generates cell density gradients from tumor edge to core. Interestingly, stem cells appear at high densities and fetal-like cells at low densities.

Could emergent mechanical gradients coordinate tumor cell state transitions?🤔

3/ Colorectal cancer organoid monolayers spontaneously recapitulate the tumor spatiotemporal patterning of stem (Lgr5) and fetal-like (Sca1) states, despite growing in homogeneous genetic and microenvironmental conditions.

Which signals pattern cell states in this context? 🤔

2/ Phenotypic heterogeneity is mainly attributed to genetic and microenvironmental factors.

However, here we show that tumors can also intrinsically coordinate the spatiotemporal patterning of cell states through mechanical signals!