Cancer research最新文献

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSC) that persist after therapy and seed treatment-refractory recurrent tumors. GBM tumors display a high degree of intra- and intertumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on a gradient between two transcriptional states or subtypes termed developmental and injury response. Drug targets for each subtype are needed to effectively target GBM. To identify conserved and subtype-specific genetic dependencies across a large and heterogeneous panel of GSCs, we designed the GBM5K-targeted guide RNA library and performed fitness screens in a total of 30 patient-derived GSC cultures. The focused CRISPR screens identified the most conserved subtype-specific vulnerabilities in GSCs and elucidated the functional dependency gradient existing between the developmental and injury response states. Developmental-specific fitness genes were enriched for transcriptional regulators of neurodevelopment, whereas injury response-specific fitness genes were highlighted by several genes implicated in integrin and focal adhesion signaling. These context-specific vulnerabilities conferred differential sensitivity to inhibitors of β1 integrin, focal adhesion kinase, MEK, and OLIG2. Interestingly, the screens revealed that the subtype-specific signaling pathways drive differential cyclin D (CCND1 vs. CCND2) dependencies between subtypes. These data provide a biological insight and mechanistic understanding of GBM heterogeneity and point to opportunities for precision targeting of defined GBM and GSC subtypes to tackle heterogeneity. Significance: CRISPR-Cas9 screens in a panel of patient-derived glioblastoma stem cells reveal heterogeneity in genetic vulnerabilities across subtypes that have important implications for targeted and combination treatment strategies for glioblastoma.

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoclasts and osteoblasts and leads to bone lesions. A deeper understanding of the processes mediating this reprogramming could help develop interventions for treating patients with bone metastases. Here, we demonstrated that osteocytes (Ot) in established breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified Ots from mice with breast cancer bone metastasis enriched in senescence, SASP markers, and pro-osteoclastogenic genes. Multiplex in situ hybridization and artificial intelligence-assisted analysis depicted Ots with senescence-associated satellite distension, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. Breast cancer cells promoted Ot senescence and enhanced their osteoclastogenic potential in in vitro and ex vivo organ cultures. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that Ots undergo pathological reprogramming by breast cancer cells and identify Ot senescence as an initiating event triggering lytic bone disease in breast cancer metastases. Significance: Breast cancer cells remodel the bone microenvironment by promoting premature cellular senescence and SASP in osteocytes, which can be targeted with senolytics to alleviate bone loss induced by metastatic breast cancer. See related commentary by Frieling and Lynch, p. 3917.

Tumor progression is an evolutionary process during which cells acquire distinct genetic alterations. Several cancer evolutionary studies reconstruct this evolutionary process by applying bulk DNA sequencing to a tumor sample to infer the presence of genetic alterations using various tumor evolutionary algorithms. Through a comprehensive benchmarking effort of these algorithms, a recent study by Salcedo and colleagues found that algorithmic and experimental choices are the main drivers of the accuracy of tumor evolution reconstruction, shedding new light on interpreting previous studies and suggesting a useful path forward for the research community.

Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation and inactivation of KEAP1, blocking subsequent ubiquitin-proteasome degradation of CHD6. Stabilized CHD6 formed a complex with p65 to establish pro-inflammatory enhancers and thereby regulate NF-κB-mediated transcription. Moreover, CHD6 recruited mSWI/SNF ATPases to maintain chromatin accessibility at CHD6-bound enhancers. The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and pro-inflammatory enhancers assembly that endows FH-deficient tumors with epigenetic vulnerabilities.

During metastasis, cancer cells detach from the primary tumor, circulate through the bloodstream, and establish themselves at distant sites, facing increased levels of reactive oxygen species (ROS) that act as significant barriers to metastatic progression. Adapting to and surviving in these high-ROS environments is thus crucial for successful metastasis. A recent study by Nease and colleagues identified FTSJ1 as the methyltransferase responsible for methylation of the U34 position wobble uridine modification of selenocysteine (Sec) tRNA. This methylation enables efficient Sec insertion, leading to increased translation of a subset of stress-responsive selenoproteins that combat the oxidative stress encountered during the metastatic process. This study establishes FTSJ1 as an essential redox regulator during metastasis through its role in enhancing Sec insertion efficiency, and introduces a potential therapeutic strategy against metastasis.

Breast cancer subtypes display different metastatic organotropism. Identification of the mechanisms underlying subtype-specific organotropism could help uncover potential approaches to prevent and treat metastasis. Herein, we found that FOXF2 promoted the seeding and proliferative recovery from dormancy of luminal breast cancer (LumBC) and basal-like breast cancer (BLBC) cells in the bone by activating the NF-κB and BMP signaling pathways. Conversely, FOXF2 suppressed the seeding and proliferative recovery of BLBC cells in the lung by repressing the TGF-β signaling pathway. FOXF2 directly upregulated RelA/p65 transcription and expression in LumBC and BLBC cells by binding to the RELA proximal promoter region, and RelA/p65 bound to the FOXF2 proximal promoter region to upregulate expression, forming a positive feedback loop. Targeting the NF-κB pathway efficiently prevented the metastasis of FOXF2-overexpressing breast cancer cells to the bone, while inhibiting TGF-β signaling blocked the metastasis of BLBC with low FOXF2 expression to the lung. These findings uncover critical mechanisms of breast cancer subtype-specific organotropism and provide insight into precision assessment and treatment strategies.

Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drug, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can impact drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.

DHX9 is a multifunctional DExH-box RNA helicase with important roles in the regulation of transcription, translation, and maintenance of genome stability. Elevated expression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC). Microsatellite instable-high (MSI-H) tumors with deficient mismatch repair (dMMR) display a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. In this report, we show that DHX9 knockdown increased RNA/DNA secondary structures and replication stress, resulting in cell cycle arrest and the onset of apoptosis in cancer cells with MSI-H/dMMR. ATX968 was identified as a potent and selective inhibitor of DHX9 helicase activity. Chemical inhibition of DHX9 enzymatic activity elicited similar selective effects on cell proliferation as seen with genetic knockdown. In addition, ATX968 induced robust and durable responses in an MSI-H/dMMR xenograft model but not in a microsatellite stable (MSS)/proficient mismatch repair (pMMR) model. These preclinical data validate DHX9 as a target for the treatment of patients with MSI-H/dMMR. Additionally, this potent and selective inhibitor of DHX9 provides a valuable tool with which to further explore the effects of inhibition of DHX9 enzymatic activity on the proliferation of cancer cells in vitro and in vivo.