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. 2024 Jun;26(6):859-867.
doi: 10.1038/s41556-024-01413-y. Epub 2024 Apr 30.

Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation

Tianchi Xin  1 , Sara Gallini  2 , Haoyang Wei  2 , David G Gonzalez  2 , Catherine Matte-Martone  2 , Hiroki Machida  3   4 , Hironobu Fujiwara  3   4 , H Amalia Pasolli  5 , Kathleen C Suozzi  6 , Lauren E Gonzalez  2 , Sergi Regot  7 , Valentina Greco  8   9   10
Affiliations

Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation

Tianchi Xin et al. Nat Cell Biol. 2024 Jun.

Abstract

Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division.

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