Oncogenic signaling is coupled to colorectal cancer cell differentiation state

TY - JOUR

T1 - Oncogenic signaling is coupled to colorectal cancer cell differentiation state

AU - Sell, Thomas

AU - Klotz, Christian

AU - Fischer, Matthias M

AU - Astaburuaga-García, Rosario

AU - Krug, Susanne

AU - Drost, Jarno

AU - Clevers, Hans

AU - Sers, Christine

AU - Morkel, Markus

AU - Blüthgen, Nils

N1 - © 2023 Sell et al.

PY - 2023/6/5

Y1 - 2023/6/5

N2 - Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.

AB - Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.

KW - Humans

KW - Cell Differentiation

KW - Colorectal Neoplasms/genetics

KW - Intestines

KW - Mutation

KW - Signal Transduction

KW - Oncogenes

U2 - 10.1083/jcb.202204001

DO - 10.1083/jcb.202204001

M3 - Article

C2 - 37017636

SN - 0021-9525

VL - 222

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 6

ER -