Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers - Nature Metastasis-associated oncofetal cell states emerge at the earliest stages of colorectal cancer and spatial profiling shows stereotypic patterning of fibroblast subtypes resembling normal tissue archit...

new out in Nature www.nature.com/articles/s41...

Very proud to share our new paper on early cancer progression, published in Nature!

Beyond the science itself, this project really shows what strong interdisciplinary collaboration can achieve. I feel grateful to have been part of this amazing team.

Check out our discoveries below!

Immense gratitude to the whole team and superior collaborators Leon Moons and Miangela Laclé.

Big thanks to our funders @erc.europa.eu KWF ZonMw @oncodeinstitute.bsky.social @umcutrecht.bsky.social @themaximacenter.bsky.social

And no, presence of oncofetal plasticity does not equate to metastatic disease 🔥 💣 🤯

Fibroblast-organoid co-cultures 🧫 confirm that these trophocyte-like CAFs induce plastic transitioning to oncofetal states. Their interaction follows from invasive growth into the submucosa and dictates the timing and location at which oncofetal plasticity first occurs during CRC progression.

Single-cell spatial atlases 🌍 of tumors pre-and post malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture. Of interest: the first cancer-associated fibroblasts resembled submucosal trophocytes and colocalize with oncofetal cells

To understand how invasive phenotypes first emerge, we generated multiregional organoid models that reflect successive tumor progression stages within individual early-stage CRCs. Whole-genome sequencing 🧬 and growth factor-dependency assays 💊 exclude tumor cell-intrinsic acquired traits.

With @julian-buissant.bsky.social @jorihag.bsky.social Sascha Brunner and Suzanne van der Horst, we pivoted our focus to the earliest stages of cancer 🔬

Malignant transformation is a milestone in tumor evolution but still a "black box"

My lab's ambition became prevention of metastatic disease 🙅

Huge news! Our research is out in Nature✨

www.nature.com/articles/s41...

We’ve uncovered that oncofetal plasticity in colorectal cancer arises far earlier than anyone expected. Providing a new lens on how cancers transition to metastatic disease.

Big thanks to my team and collaborators!

I’m happy to share our new preprint on stem cell regeneration in the human colon! Using new CRISPR knockins in organoids, we show that after stem cell loss, non-stem cells rapidly regenerate them. This process is normally inhibited by the stem cells themselves. Manuscript link: tinyurl.com/3ky4ccxf

6/ Many thanks to all co-authors, dear collaborators and funders. Especially the Dutch Research Council (NWO) for our ‘organoids in time’ consortium spearheaded by Jeroen van Zon

5/ Our tuft subtype-specific reporters and optimized differentiation strategy in organoids provide an experimental platform to study immune-related tuft cell subtypes and their unique cell biological properties, like signal perception, processing and transmission to trigger immune defense.

4/ Adaptation of the crypt-like organoid medium to better mimic the villus environment, where tuft-2 cells reside in vivo, facilitates transitioning of post-mitotic immature tuft-1 states to the mature immune-related tuft-2 states that is ready for in-depth cell biological studies.

3/ Organoids with subtype-specific reporter knock-ins show that known tuft types in fact reflect successive maturation stages within the tuft lineage. Be aware 😱, commonly applied organoid treatment with IL-4 and 13 does lead to increased tuft numbers, but solely generates early tuft-1 states 🙅❌

2/ We analyzed single-cell intestinal tuft cell transcriptomes from mouse and human to reveal conserved proliferative tuft cell precursors (tuft-p), as well as abundant intermediaries of the previously described post-mitotic tuft-1 and tuft-2 cell states.

🔊 Paper alert
1/ Tuft cells are perhaps the coolest cells in our gut orchestrating host defense, but how do they manage? @julian-buissant.bsky.social provides new insights into tuft cell differentiation, and the development of accurate in vitro models for experimental cell biology 🧫🔬🧬
rdcu.be/exou9

Thanks for the compliments Adam

Big thanks to all our co-authors and in particular @jorihag.bsky.social for conceiving and spearheading this cool project 👏👏 🙌 💪

8/ Thus, stem cell-derived retinoic acid actively suppresses plasticity in colonocytes, ensuring homeostasis and explaining how surviving cells sense stem cell loss. Please see preprint for detailed info. Concerning our favoured knock-in strategy, please see Bollen, Hageman et al., PLOS Biol 2022

7/ Under homeostatic conditions, RXR is activated in colonocytes by RA produced by ALDH in stem cell compartments. But when the RA signal is lost (via stem cell loss or RXR inhibition), cells switch to an ANXA1-high regenerative state (visualized by independent ANXA1-RFP knock-in)

6/ scRNA-seq and sc-multiome at high temporal resolution showed that predominantly surviving colonocytes first adopt a regenerative state marked by high ANXA1, before giving rise to new stem cells.

5/ Stem cell depletion triggered an unbiased and fast response with surviving cells quickly regenerating the LGR5+ stem cell pool. (normal organoids carrying 2 knock-ins: LGR5-GFP-DTR x KRT20-RFP-iCasp9)

4/ Next, knock-in of the Diphtheria Toxin Receptor into the LGR5 locus enabled selective stem cell ablation under normal conditions. Killing was robust, consistent and independent of low expression levels common to typical cell type markers (unlike inducible iCasp9)

3/ First, we harnessed the power of genetic mouse models with selective cell type ablation. Except 😥, the widely used Diphtheria Toxin Receptor for cell killing is a common human receptor. 💡 We de-sensitised human organoids for D with a murinizing 🐭 point mutation in the endogenous entry factor.

2/ We found that human colon stem cells produce retinoic acid (RA), which acts as a “keep calm and carry on” signal to neighbouring cells, actively blocking their entry into a regenerative state. It explains how surviving cells sense stem cell loss 🔥

📢 New preprint 🔥
1/ Stem cell regeneration is often viewed as an actively induced process, triggered by damage. But what if plasticity is actively suppressed by the stem cells themselves? We explored plasticity with 'new' cell type ablation tech in normal human colon organoids
tinyurl.com/3ky4ccxf

Our #Cancer #Evolution summer school runs again 30 June-3 July at the beautiful Genome Campus in Hinxton, UK sponsored by @wellcometrust.bsky.social

Ideal for starters in the field; this year's focus is on using genomic data for cancer evo research.

Brilliant & inspiring faculty! bit.ly/40nLdDD

📢 Organoid enthusiast: We are preparing for the 3rd edition of OrganoidNL - April 11th!
🔥 Check amazing line up of speakers 🔥
Calvin Kuo @priscaliberali.bsky.social Nicolas Rivron, Ina Sonnen @kaikretzschmar.bsky.social Mina Gouti, and others. Be fast to register in time
amolf.nl/organoidnl-s...

Massive congrats to Shania, Svetlana & Noha (not on Bsky) identifying the mechanistic and phenotype cascades underpinning the anti-metastatic response triggered by viral mimicry

TLDR; aggressive CMS4 tumours can be reprogrammed towards less aggressive CMS1

biorxiv.org/content/10.1...

thread 👇

Very happy that our tuft cell story is now on BioRxiv! If you want to know how to induce mature tuft cell phenotypes in organoids check out the preprint