Nature cancer最新文献

Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNA^Sec isodecoders differing by a single 2'-O-ribose methylation called Um34. Here we characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and show decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNA^Sec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.

Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination.

Although the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumors at presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping as orthogonal methods for lineage tracing. In four patients, developmental mosaicism, assessed by WES and poly(G) lineage tracing, indicates a common non-germline cell of origin. In two other patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. Thus, in addition to germline variants, developmental mosaicism defines a distinct mechanism of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for their etiology and clinical management.

Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1^-/-; Trp53^-/-; cMyc⁺ or Pten^-/-; Trp53^-/-; cMyc⁺) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1⁺ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1⁺ cells arise from KRT8⁺ luminal cells, progressing into transcriptionally heterogeneous ASCL1⁺;KRT8^- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.

Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.