Oncofetal cell states: cell plasticity drives invasion in premetastatic colorectal tumors

Abstract

In a recent publication in Nature , Buissant des Amorie et al. provide evidence that an oncofetal cell state which is associated with advanced disease, chemoresistance and metastatic competence emerges already in early-stage T1 colorectal cancer (CRC). Intriguingly, oncofetal cell states at the invasive front are in close proximity to an exclusive subcluster of cancer-associated fi bro-blasts (CAFs) thus arguing that cell plasticity towards an oncofetal state is governed by non-cell-autonomous mechanisms. 1 Oncofetal cells arise when cancer cells hijack the fetal-like regenerative programs normally activated during intestinal injury, acquiring highly plastic cellular states distinct from canonical LGR5 ⁺ stem cells. 2 In CRC, oncofetal states exist along a continuum with stem-like states and are shaped by both tumor-intrinsic genetic alterations and signals from the tumor microenvironment. 3,4 Acquisition of regenerative oncofetal states is increasingly recognized as an important mechanism that enhances metastatic competence, invasion, therapy resistance, and survival under stress. By inducing a slow-cycling phenotype, the oncofetal cell transition confers resistance to antimitotic therapies, enhancing cancer cell survival and increasing the risk of relapse. 5 Buissant des Amorie et al. now performed spatial transcriptomic pro fi ling of early-stage T1 CRC specimens and identi fi ed fetal-like gene expression signatures, including EMP1, MMP7, LAMC2, and ANXA1, at the invasive front, which were associated with a high risk of relapse. The detection of metastasis-associated transcriptional programs in these early-stage tumors was unexpected and led to validation in a larger patient cohort. To this end, the authors analyzed 232 T1 CRC