Cancer research最新文献

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. In this study, we found that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." Analysis of public human breast tumor single-cell RNA sequencing datasets and histopathologic breast tumor specimens, as well as functional experiments in vitro in breast cancer cell lines and in vivo in murine transgenic and cell line-derived mammary cancer models, showed that neoplastic cells engaged in immune mimicry. Immune-mimicked neoplastic cells harbored hallmarks of dedifferentiation and were enriched in treatment-resistant and high-grade breast tumors. In aggressive breast cancer cell lines, antiproliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. The expression of the CD69 leukocyte activation protein by neoplastic cells conferred a proliferative advantage that facilitated early tumor growth. Together, these findings suggest that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy and that neoplastic immune mimicry has potential clinical utility for patient prognosis and stratification.

Significance: A subset of neoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stroma that profoundly influences tumor biology and therapeutic response. Cancer-associated fibroblasts (CAF), the major stromal component, exist as heterogeneous populations with both tumor-promoting and tumor-restraining functions. In this issue of Cancer Research, Manoukian and colleagues uncover a previously unrecognized hormonal axis in PDAC, demonstrating that estrogen signaling reprograms fibroblast identity and shapes the tumor microenvironment. Building on prior work identifying an inflammatory CAF subset marked by high OGN and CLEC3B expression (iCAF.1) and associated with favorable prognosis, the authors show that estrogen produced by cancer cells promotes this tumor-restraining phenotype while limiting myofibroblastic CAF activation. Reciprocally, CAF-derived branched-chain amino acids taken up by cancer cells via SLC25A44-mediated uptake fuel estrogen biosynthesis, creating a feedback loop that sustains the classical, less aggressive PDAC subtype. Collectively, these findings establish estrogen as a key modulator of CAF heterogeneity and highlight a novel mechanism of tumor-stroma cross-talk with potential therapeutic implications for stroma-directed interventions in pancreatic cancer. See related article by Manoukian et al., p. 571.

Cancer-associated fibroblasts (CAFs) play a crucial role in shaping the tumor microenvironment (TME) and driving tumor progression. While single-cell transcriptomics has revealed the phenotypic and functional heterogeneity of CAFs, effective therapeutic strategies targeting CAFs remain urgently needed. Here, we identified LRRC15+ CAFs as a tumor-specific CAF subset in lung cancer and proposed LRRC15 as a potential therapeutic target. LRRC15 deficiency suppressed lung cancer progression in mice by modulating macrophage polarization and enhancing CD8+ T cell activation. Mechanistically, LRRC15 deficiency inhibited CD206+ macrophage polarization by reducing extracellular matrix (ECM) production in CAFs, leading to increased CD8+ T cell cytotoxicity. Finally, development of a bispecific antibody targeting LRRC15 and TGF-β enabled effective downregulation of LRRC15 expression in CAFs and limited tumor progression in mice. This study highlights LRRC15 as a promising therapeutic target and provides insights into CAF-directed cancer treatment strategies.

Colorectal cancer (CRC) is characterized by a complex tumor microenvironment (TME) shaped by intestinal microbiota. In this study, 16S rRNA sequencing of CRC patient tissues identified Prevotella, particularly the dominant species Prevotella copri (P. copri), as a key intratumoral bacterium. The parenchymal invasion of P. copri was confirmed by fluorescence in situ hybridization (FISH), and the abundance of P. copri correlated with advanced tumor stages and postoperative serological markers. Notably, the reduced abundance of P. copri in paired normal tissues implied potential bacterial translocation during tumorigenesis. In multiple murine models, P. copri not only accelerated tumor growth but also reprogrammed tumor-associated macrophages (TAMs) toward a pro-tumoral state. Untargeted metabolomics revealed glycerophosphocholine (GPC) as the only conserved metabolite depleted by P. copri across murine models and bacterial cultures, a finding confirmed by spatial metabolomics in clinical specimens. Strikingly, GPC supplementation reprogrammed MARCO+ TAMs toward an anti-tumoral phenotype, effectively counteracting P. copri-mediated tumor progression. Overall, this study uncovers a paradigm in CRC pathogenesis in which P. copri creates an immunosuppressive niche by depleting GPC to manipulate macrophage polarization. These findings position P. copri as both a non-invasive diagnostic marker and druggable therapeutic target, with GPC restoration representing a promising immunometabolic intervention strategy.

Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer with survival time of only 7-10 months. Previous work revealed reduced proportions and cytotoxicity of natural killer (NK) cells in ATC tumor microenvironment (TME). Here, we investigated the role of super-enhancers (SEs), clusters of adjacent enhancers and drive high expression of genes, in reshaping the TME in ATC. Comprehensive profiling of the SE landscapes in ATC revealed activation of oncogenic SEs as a mechanism underlying the dedifferentiation and anaplastic transformation of thyroid cancer. An SE signature based on recurrent SEs in ATC was associated with significantly shortened overall patient survival. FOSL1 was identified as an SE-driven transcriptional factor that was crucial for epigenetic remodeling of ATC cells. Interestingly, FOSL1 bound to its own SE, promoted chromatin looping and spatial proximity of the distal SE with its promoter, and maintained its high expression, forming a positive feedback self-regulation circuit. During ATC progression, FOSL1 boosted expression of metalloproteinases ADAM9 and MMP14 via binding to their SEs, which promoted MICA shedding from the cell surface and led to subsequent immune escape from NK cell killing. Silencing FOSL1, ADAM9, or MMP9 sensitized ATC cells to NK cell-mediated cytotoxicity in vitro and suppressed ATC growth in vivo. Together, these findings highlight the role of FOSL1 in chromatin remodeling of ATC and in dampening cytotoxic functions of NK cells, thereby providing insights into the development of potential cancer therapeutics.

Therapeutic resistance to DNA damage is a significant challenge in oncology. To gain insight into biological mechanisms that cause DNA damage resistance and to inform strategies for achieving synergy with therapeutic radiation, we performed parallel pooled genetic CRISPR-Cas9 screening for survival in high-risk head and neck squamous cell carcinoma (HNSCC) subtypes. Surprisingly, in addition to known mediators of radiotherapy response, including ATM, DNAPK, and NF-κB signaling, loss of JAK1 was identified as a driver of tumor cell radioresistance. Knockout of JAK1 in HNSCC increased cell survival by enhancing the DNA damage-dependent G2/M cell cycle arrest and delaying progression to radiation-induced mitotic catastrophe. In line with this finding, both JAK1 knockout and kinase inhibition with abrocitinib prevented subsequent formation of radiation-induced micronuclei. Loss of JAK1 function did not affect canonical CDK1 signaling but instead reduced activation of PLK1 and AURKA, two kinases with auxiliary roles in the regulation of G2 and M phase progression. Correspondingly, using both EdU labelling and live cell imaging techniques, JAK1 loss was found to cause prolonged metaphase, mitotic slippage, and progression to tetraploidy. Targeting the mitotic kinesin KIF18A with the small molecule sovilnesib exacerbated mitotic stress and enhanced the efficacy of radiation. These studies establish KIF18A inhibition as a strategy to counteract the protective G2/M cell cycle arrest induced by DNA damage and to thus enhance tumor cell sensitivity to radiation therapy.