It is demonstrated that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1+ tumor stem cells.
Abstract
Plasticity, the capability of tumor cells to go through phenotypic transitions, promotes colorectal cancer (CRC) progression and treatment resistance. Although plasticity is evident in advanced CRCs, little is known about plasticity in early-stage tumors and tumor stem cells. Here, we demonstrate that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1+ tumor stem cells. We furthermore analyzed progressive plasticity upon loss of the canonical wingless-related integration site (Wnt) effector Tcf7 or Lef1 in Apc mutant mice. Deletion of either gene led to emergence of new plastic tumor cell populations, failure of leucine-rich repeat–containing G protein-coupled receptor 5 (Lgr5) tumor stem cell differentiation into enterocyte-like cells, enhanced Myc pathway activation, and increased tumor cell proliferation and tumorigenesis. Together, we demonstrate that PCS is associated with early CRC development and identify multiple potentially druggable mechanisms activated during progressive tumor cell plasticity.
These findings identify a tumor-adapted MC state that orchestrates immune evasion and tissue remodeling during CRC progression, supporting the notion that MC are reprogrammed toward an immune-suppressive and pro-tumorigenic phenotype.
E. Putro, Alessia Carnevale, Caterina Marangio et al.· Cell Death & Disease· 0 citations
This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Jia Li, Jinling Li, Yuechao Zhao et al.· Frontiers in Immunology· 0 citations
This review consolidates emerging evidence that positions cell competition as a critical regulator of clonal dynamics within the breast cancer TME and identifies competitive cellular fitness as a central and targetable driver of therapeutic resistance and tumor recurrence in breast cancer.
Esha Pal, Sovan Chakraborty, A. Guha· Frontiers in Oncology· 0 citations
It is shown that KRASG12D mutations in lung epithelium drive proliferation of resident, embryonically-derived alveolar macrophages, which then promote tumor cell proliferation and protection from ferroptosis, leading to tumor progression.
Jaroslav Zak, Hui Chen, Erpei Wang et al.· bioRxiv· 0 citations
A GSTT1HighCD133High stem-like subpopulation in metastatic PDA is identified and an FGFR-dependent signaling axis that sustains this state is identified, representing a potential therapeutic vulnerability.
D. de la Caridad Delgado Herrera, Alejandro Arroyo Roman, Riyan N. Campbell et al.· Cancer Letters· 0 citations
Breast cancer is a heterogeneous disease in which a single oncogenic driver can give rise to divergent tumor phenotypes. How oncogenic mutations generate epithelial state plasticity and coordinately remodel the surrounding tissue remains incompletely understood. Here, we applied longitudinal single cell RNA-sequencing to trace the mammary landscape during Pik3caH1047R-driven tumor progression in the mouse. We identify an expansion of the epithelial transcriptional state space, in which luminal cells lose lineage fidelity and activate ciliated, basal, and squamous-like gene expression programs. While oncogene-expressing cells lose features of luminal identity, they retain expression of hormone-sensing genes such as Esr1, Pgr, and Foxa1. These transcriptional states are established early, and the transition to overt tumors is marked by the emergence of cancer-associated fibroblasts rather than new epithelial states. We identify a Postn+ fibroblast population enriched at the epithelial interface as a candidate progenitor of cancer-associated fibroblasts. Postn+ fibroblasts express an ECM-remodeling program and display altered epithelial crosstalk in oncogenic glands. Altogether, Pik3caH1047R activation initiates a tissue-level process beginning with epithelial lineage infidelity, followed by an altered stromal microenvironment, which together mark tumor initiation.
Jennifer T. Le, Eun K. Kim, Vasudha Srivastava et al.· bioRxiv· 0 citations