Cancer research最新文献

The batch effect is a nonbiological variation that arises from technical differences across different batches of data during the data generation process for acquisition-related reasons, such as collection of images at different sites or using different scanners. This phenomenon can affect the robustness and generalizability of computational pathology- or radiology-based cancer diagnostic models, especially in multicenter studies. To address this issue, we developed an open-source platform, Batch Effect Explorer (BEEx), that is designed to qualitatively and quantitatively determine whether batch effects exist among medical image datasets from different sites. A suite of tools was incorporated into BEEx that provide visualization and quantitative metrics based on intensity, gradient, and texture features to allow users to determine whether there are any image variables or combinations of variables that can distinguish datasets from different sites in an unsupervised manner. BEEx was designed to support various medical imaging techniques, including microscopy and radiology. Four use cases clearly demonstrated the ability of BEEx to identify batch effects and validated the effectiveness of rectification methods for batch effect reduction. Overall, BEEx is a scalable and versatile framework designed to read, process, and analyze a wide range of medical images to facilitate the identification and mitigation of batch effects, which can enhance the reliability and validity of image-based studies. Significance: BEEx is a prescreening tool for image-based analyses that allows researchers to evaluate batch effects in multicenter studies and determine their origin and magnitude to facilitate development of accurate AI-based cancer models.

Central nervous system neuroblastoma with forkhead box R2 (FOXR2) activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2-specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 tumors originate from LHX6+/DLX+ interneuron lineages, a lineage of origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics. Significance: Profiling the developing brain enabled rationally guided modeling of FOXR2-activated CNS neuroblastoma, providing a strategy to overcome the heterogeneous origins of pediatric brain tumors that hamper tumor modeling and therapy development. See related commentary by Orr, p. 195.

Several therapeutic agents have been approved for treating multiple myeloma, a cancer of bone marrow-resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. In this study, we present an integrated functional genomic analysis of tumor samples from patients multiple myeloma that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes. This analysis revealed a multiple myeloma transcriptomic topology that generates "footprints" in association with ex vivo drug sensitivity that have both predictive and mechanistic applications. Validation of the transcriptomic footprints for the anti-CD38 mAb daratumumab (DARA) and the nuclear export inhibitor selinexor (SELI) demonstrated that these footprints can accurately classify clinical responses. The analysis further revealed that DARA and SELI have anticorrelated mechanisms of resistance, and treatment with a SELI-based regimen immediately after a DARA-containing regimen was associated with improved survival in three independent clinical trials, supporting an evolutionary-based strategy involving sequential therapy. These findings suggest that this unique repository and computational framework can be leveraged to inform underlying biology and to identify therapeutic strategies to improve treatment of multiple myeloma. Significance: Functional genomic analysis of primary multiple myeloma samples elucidated predictive biomarkers for drugs and molecular pathways mediating therapeutic response, which revealed a rationale for sequential therapy to maximize patient outcomes.

T-cell exhaustion remains a significant barrier to immunotherapeutic success for many patients with solid tumors. Growing evidence suggests that enhanced survival and self-renewal properties of a stem-like precursor T-cell population are correlated with a survival advantage in immunotherapy. In a recent study published in Science, Kang and colleagues found that three epigenetic regulators commonly mutated in clonal hematopoiesis also control precursor T-cell progression to exhaustion. By leveraging the finding that patients with enhanced survival in myelodysplastic syndrome had T-cell mutations in the ASXL1 gene, this study demonstrates that loss of ASXL1 in T cells preserves their stem cell-like properties of self-renewal and survival, leading to increased antitumor responses when combined with immunotherapy in both mouse models and human cancers. These findings have significant implications for new therapeutic options that target epigenetic modifiers promoting exhaustion together with immune checkpoint blockade to improve response rates in patients.

Mouse models that faithfully represent the biology of human brain tumors are critical tools for unraveling the underlying tumor biology and screening for potential precision therapies. This is especially true of rare tumor types, many of which have correspondingly few xenograft or cell lines available. Although our understanding of the specific biological pathways driving cancer has improved significantly, identifying the appropriate progenitor populations to drive oncogenic processes represents a significant barrier to efficient mouse model production. In this issue of Cancer Research, Jessa and colleagues developed an innovative transcription factor fingerprinting method to map the cellular origin of central nervous system neuroblastoma, FOXR2-activated to medial ganglionic eminence-derived interneurons, which could then be efficiently targeted in the developing mouse brain using in utero electroporation. This approach serves as a blueprint for investigating other rare pediatric brain tumors, potentially accelerating progress toward the development of mouse models and identification of effective therapies. See related article by Jessa et al., p. 231.

Overexpression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. Although PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic BRAFV600E also promoted PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, depletion of PHGDH in genetic mouse melanoma models blocked tumor formation. In addition to BRAFV600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction. Consequently, melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction, which promoted cell death in vitro and attenuated melanoma growth in vivo. In summary, this study identified that PHGDH is essential for melanomagenesis and regulated by BRAFV600E, revealing a targetable vulnerability in BRAFV600E-mutant melanoma. Significance: BRAFV600E promotes the expression of the serine synthesis enzyme PHGDH, which is required for melanoma formation, and can be targeted to sensitize melanoma to dietary serine restriction, providing a melanoma cell-specific treatment strategy.

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. In this study, we used next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and angiotensin-converting enzyme 2 (ACE2) expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune-competent mice. Mass cytometry by time of flight revealed that ACE2-deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages, displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor-intrinsic chemokine (C-C motif) ligand 5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower chemokine (C-C motif) ligand 5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacologic targeting of CCR5 using maraviroc enhanced the tumor-suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade. Significance: ACE2 regulates the immune landscape of hepatocellular carcinoma by abrogating M2-like macrophage polarization and sensitizes tumors to anti-PD-L1, suggesting that harnessing the ACE2 axis could be a promising strategy to improve immunotherapy efficacy.

Radiotherapy is an integral component in the treatment of many types of cancer, with approximately half of cancer patients receiving radiotherapy. Systemic therapy applies pressure that can select for resistant tumor subpopulations, underscoring the importance of understanding how radiation impacts tumor evolution to improve treatment outcomes. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA (ctDNA) analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPS displayed initial linear evolution followed by subsequent branching evolution with distinct mutational processes during early and late development. Metrics of genetic divergence between regions provided evidence of strong selection pressures during UPS development that further increased during radiotherapy. Subclone abundance changed following radiotherapy with subclone contraction tied to alterations in calcium signaling, and inhibiting calcium transporters radiosensitized sarcoma cells. Finally, ctDNA analysis accurately measured subclone abundance and enabled non-invasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPS and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy.