Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion

Single-cell RNA sequencing reveals pro-tumorigenic intestinal mast cell programs in colorectal cancer

Mast cells (MCs) are multifunctional immune cells with context-dependent functions in cancer. In colorectal cancer (CRC), their contribution remains debated, suggesting that distinct MC subsets may either support tumor progression or promote anti-tumor immunity. Using single-cell RNA sequencing in a mouse model of inflammation-driven CRC, we uncovered extensive MC plasticity during tumor progression. Transcriptomic profiling and pseudotime trajectory analysis revealed a transition from precursor-like MCs exclusively present in adjacent tissue to differentiated tumor-associated MC (TAMC) subsets. TAMCs displayed a distinct repertoire of proteases and pro-inflammatory cytokines, contributing to increased vascular permeability and recruitment of additional immune cells. Moreover, TAMCs exhibited upregulation of molecules with immunosuppressive potential and underwent a tumor microenvironment (TME)-driven metabolic reprogramming. Accordingly, antibody-mediated MC depletion reduced tumor burden. Notably, most of the transcriptional features identified in a murine CRC model were recapitulated in human CRC, supporting the translational relevance of this MC program. Our 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.

Tumor-associated macrophages and lineage plasticity in prostate cancer: from established myeloid programs to emerging spatial hypotheses

Androgen receptor signaling inhibitors (ARSIs) have transformed the treatment of advanced prostate cancer, yet durable responses are limited by the emergence of therapy-resistant disease states, including neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC). Lineage plasticity has traditionally been studied from a tumor-cell-intrinsic perspective, but single-cell and spatial studies increasingly indicate that the tumor microenvironment, particularly tumor-associated macrophages (TAMs), may influence tumor-cell state transitions, immune exclusion, and therapeutic resistance. In this review, we synthesize established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity. We first summarize independently supported myeloid programs, including SPP1+/TREM2+ macrophage states and TAM-derived pathways such as IL-6/STAT3, TGF-beta, NF-kappaB, CXCL12/CXCR4, and adenosine signaling. We then discuss PLAC8+ TAMs, TNFAIP8L2, and PLAC8+ TAM/CXCL12+ iCAF/CD8+ TRM spatial aggregates as an emerging, hypothesis-generating framework that may be associated with ARSI-induced DNPC-like remodeling. Importantly, we explicitly distinguish spatial and transcriptomic associations from experimentally proven causal mechanisms. The proposed TNFAIP8L2-integrin/PI3K-Akt/beta-catenin/FOSL1-HMGA1 cascade is therefore presented as a working model that requires direct biochemical, genetic, and in vivo validation. Finally, we outline an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.

Cell competition within breast tumor microenvironment: emerging role of cancer stem cells and immune cells in tumor progression and therapeutic implications

Breast cancer remains the most prevalent malignancy among women worldwide, with approximately 2.3 million new cases diagnosed annually, accounting for nearly 12% of all cancer diagnosis globally. Increasing evidence highlights the tumor microenvironment (TME) as a dynamic and interactive ecosystem that governs tumor behaviour. This review consolidates emerging evidence that positions cell competition as a critical regulator of clonal dynamics within the breast cancer TME. We examine how breast cancer stem cells (BCSCs), defined by CD44+/CD24- phenotype and elevated ALDH activity, acquire enhanced fitness through MYC amplification and dysregulation of Hippo/YAP, Wnt/β-catenin and Notch signaling pathways. In parallel, we analyze the role of immune cell populations including tumor-associated macrophages, cytotoxic T lymphocytes, natural killer cells and myeloid-derived suppressor cells in shaping competitive interactions through resource limitation and immuno-suppressive signaling. We further explore metabolic competition, highlighting the Warburg effect, reverse Warburg effect and lactate-mediated immuno-suppression as central regulators of cellular fitness, alongside contributions from cancer-associated fibroblasts, extracellular matrix remodeling and exosome-mediated communication. The novelty of this study lies in integrating cellular, metabolic and stromal dimensions of competition into a unified framework and extending the concept beyond tumor cells to include immune and non-cellular components. Cumulatively, this study identifies competitive cellular fitness as a central and targetable driver of therapeutic resistance and tumor recurrence in breast cancer.

An IL-34–IGF-1 inflammatory axis fuels KRAS-mutant lung cancer progression

GSTT1 promotes stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 (PROM1).

Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133HighGSTT1High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1HighCD133High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.

Longitudinal single cell RNA-sequencing of Pik3caH1047R-driven mammary tumorigenesis reveals coordinated transformation of epithelial and fibroblast transcriptional states

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.