Highlighted Research Articles

Despite the consideration that chemotherapy during pregnancy is safe for both mother and child, its mutagenic effects on the fetal genome remain uninvestigated. Therefore, Struys and colleagues evaluated the mutational effects of prenatal chemotherapy exposure and found that several chemotherapy regimens were associated with an increase in mutation burden in neonatal hematopoietic stem cells. Underlying mutational signatures resembled those seen in cancer survivors treated with similar regimens. The findings suggest that prenatal chemotherapy exposure may induce mutations in fetal cells, emphasizing the need for further research on the genomic impact of perinatal environmental insults and their long-term health consequences.See article, p. 903.Elements of healthy tissue architecture generally limit tissue plasticity and serve as barriers to tumor progression. Fibro-inflammatory programs perturb these stromal and structural elements, enabling loss of normal tissue homeostasis during early tumorigenesis. Precise mechanisms by which normal stromal states limit tissue plasticity and tumorigenesis remain largely unknown. By analyzing transcriptional programs in healthy and tumor-associated pancreatic mesenchyme, Oñate and colleagues found that a subpopulation of mesenchymal cells in healthy pancreas tissue expressed the paracrine cue stem cell factor (KITL). Loss of mesenchymal KITL is an accompanying and permissive feature of pancreas tumor evolution, with potential implications for cancer interception.See article, p. 913.Treatment with PGV001, a novel, fully personalized, multi-peptide neoantigen cancer vaccine, was found to be safe and immunogenic in a phase I clinical study. The vaccine was administered to 13 patients across multiple histologies in the absence of tumor but with a high chance of recurrence. At 5-year follow-up, six patients were alive, three of which were recurrence-free. In-depth immune profiling revealed that the vaccine induced T cell–and B cell–driven immune responses in all treated patients, with enhanced immune responses in surviving patients, indicating a possible correlation between vaccine-driven immunity and overall survival.See article, p. 930.Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have transformed renal cell carcinoma (RCC) treatment; however, the mechanisms driving resistance remain largely unknown. Hugaboom and colleagues investigated bulk and single-cell transcriptomes from RCC tumors of treatment-naïve patients, both prior to and at resistance to nivolumab monotherapy. Their results reveal that an optimal response to PD-1 blockade requires a tumor microenvironment featuring abundant tertiary lymphoid structures and minimal exhausted tissue-resident CD8+ T cells. These findings identify key determinants of anti−PD-1 efficacy in RCC and inform the development of rational combination approaches to overcome therapeutic resistance.See article, p. 948.Treatment resistance due to acquired genomic alterations and lineage transitions drives metastatic prostate cancer mortality. Utilizing a high-purity circulating tumor cell (CTC) isolation approach, Sharifi and colleagues collected CTCs from 117 patients with metastatic prostate cancer for RNA sequencing and identified CTC phenotypes mirroring lineage states identified in tissue. Patients with a luminal-B-like CTC phenotype, defined by persistent androgen receptor signaling and high proliferation, as well as those with a neuroendocrine CTC phenotype, had significantly shorter survival than patients with luminal-A-like and low proliferation phenotypes. In a prospective substudy, a pre-treatment CTC luminal-B-like phenotype was associated with early progression on lutetium-177–PSMA-617.See article, p. 969.Yamaguchi and colleagues assembled a cohort of 666 localized prostate cancers with deep DNA whole-genome sequencing. They used this resource to define a compendium of 223 somatic driver regions, most invisible to typical targeted DNA sequencing. These driver mutations rewired cancer gene–expression. A subset of early driver mutations predisposed prostate cancers to evolve specific clinical features, including grade. Interpatient heterogeneity in driver mutations was partially explained by differences in the germline genome, with widespread germline–somatic interactions. These results rationalize long-standing ancestry-related differences in prostate cancer and provide a model for the evolution of prostate tumors of different grade and lethality.See article, p. 988.Through in vivo modeling and integrative systems biology, Mavuluri and colleagues identified a pH-sensing G protein–coupled receptor (GPCR), GPR65, as a determinant of B-ALL antigen-independent resistance to CAR T-cell therapy. Notably, loss of GPR65 in a tumor signaled resistance. Comparative analysis of the clinical and preclinical tumor microenvironment (TME) emphasized enrichment of immunosuppressive M2 macrophages tethered to the VEGF–FOXO1 signaling axis in the TME of GPR65-low or -negative tumors. This discovery paves the way for targeting tumor-intrinsic GPCR signaling, VEGFA, or host macrophages to enhance immunotherapy efficacy and the use of GPR65 as a potential biomarker for predicting responses to immunotherapy in hematologic malignancies.See article, p. 1018.This study by Arenillas and colleagues explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. Tumors from chronically hypoxic patients exhibited impaired DNA repair and a high frequency of EPAS1 mutations (90%), mirroring the extreme selection of EPAS1 variants in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations upregulated COX4I2 expression, reducing oxygen consumption and promoting tumor proliferation. Clinical data revealed tissue-specific and time-sensitive tumorigenic effects in oxygen-sensitive cells postnatally. These findings underscore genetic adaptation in natural populations as a source of insight into cancer biology and potential therapeutic vulnerabilities.See article, p. 1037.The LINE-1 retrotransposon is active in many cancers including pancreatic ductal adenocarcinoma (PDAC). You and colleagues identified a function of LINE-1 ORF1 protein (LINE-1 ORF1p) outside of the canonical role in retrotransposition, whereby LINE-1 ORF1p shields viral-like repeat RNAs from activating innate immune responses to double-stranded RNA species. Suppressing LINE-1 ORF1p triggered innate immune responses that led to reduced tumor growth and epithelial–mesenchymal transition (EMT). High LINE-1 ORF1p expression correlates with poor prognosis in patients with PDAC, suggesting a role in tumor aggressiveness and immune evasion. LINE-1 ORF1p is a potential therapeutic target to enhance tumor intrinsic and extrinsic immune responses.See article, p. 1063.