Nature Cancer

Journal: Nature Cancer

Abbreviation

Nat Cancer

Publisher

Nature

ISSN

2662-1347

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Publications 1 - 10 of 10

Past, present and future of drug conjugates for cancer therapy
Cazzamalli, Samuele; Puca, Emanuele; Neri, Dario (2025)
Nature Cancer
Drug conjugates have emerged as promising tumor-targeted cytotoxics with an improved therapeutic index compared to classical chemotherapeutics. Although traditionally based on antibody ligands, high-throughput screening methods, such as peptide display and DNA-encoded chemical libraries, have enabled the isolation of ultra-high-affinity small ligands and the generation of drug conjugates with better tumor-targeting performance. This Perspective examines the history, major clinical milestones and future of drug conjugates for cancer treatment. We also discuss a new wave of combination modalities, linker strategies, and the development of conjugates based on large and small delivery vehicles.
Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myeloma
Kropivsek, Klara; Kachel, Paul; Goetze, Sandra; et al. (2023)
Nature Cancer
Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.
A roadmap of therapeutic strategies for patients with multiple myeloma
Snijder, Berend; Kropivsek, Klara (2023)
Nature Cancer
Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.
Three-dimensional imaging mass cytometry for highly multiplexed molecular and cellular mapping of tissues and the tumor microenvironment
Kuett, Laura; Catena, Raúl; Özcan, Alaz; et al. (2022)
Nature Cancer
A holistic understanding of tissue and organ structure and function requires the detection of molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous detection of up to 40 antigens and transcripts using metal-tagged antibodies but has so far been restricted to two-dimensional imaging. Here we report the development of 3D IMC for multiplexed 3D tissue analysis at single-cell resolution and demonstrate the utility of the technology by analysis of human breast cancer samples. The resulting 3D models reveal cellular and microenvironmental heterogeneity and cell-level tissue organization not detectable in two dimensions. 3D IMC will prove powerful in the study of phenomena occurring in 3D space such as tumor cell invasion and is expected to provide invaluable insights into cellular microenvironments and tissue architecture.
A targetable type III immune response with increase of IL-17A expressing CD4⁺T cells is associated with immunotherapy-induced toxicity in melanoma
Dimitriou, Florentia; Cheng, Phil F.; Saltari, Annalisa; et al. (2024)
Nature Cancer
Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4(+) T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4(+) T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4(+) T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events.
Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia
Lu, Junyan; Cannizzaro, Ester; Meier-Abt, Fabienne; et al. (2021)
Nature Cancer
Chronic lymphocytic leukemia (CLL) has a complex pattern of driver mutations and much of its clinical diversity remains unexplained. We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex vivo drug response data from 217 patients with CLL. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to known biomarkers. We validated its presence and clinical relevance in four independent cohorts (n = 547 patients). We found that this axis captures the proliferative drive (PD) of CLL cells, as it associates with lymphocyte doubling rate, global hypomethylation, accumulation of driver aberrations and response to pro-proliferative stimuli. CLL–PD was linked to the activation of mTOR–MYC–oxidative phosphorylation through transcriptomic, proteomic and single-cell resolution analysis. CLL–PD is a key determinant of disease outcome in CLL. Our multi-table integration approach may be applicable to other tumors whose inter-individual differences are currently unexplained.
Multidimensional analysis reveals predictive markers for CAR-T efficacy
Letscher, Kevin P.; Reddy, Sai T. (2024)
Nature Cancer
At present, six CAR-T therapies are FDA approved to treat hematological cancers, but not all patients respond. A new study has developed a multidimensional functional profiling method to screen CAR-T cells from patients with large B cell lymphomas in clinical trials and identified a T cell subset associated with successful clinical response.
A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage
Zou, Xueqing; Koh, Gene Ching Chiek; Nanda, Arjun S,; et al. (2021)
Nature Cancer
Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR–Cas9 knockouts (∆) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage and performed whole-genome sequencing of 173 subclones. ∆OGG1, ∆UNG, ∆EXO1, ∆RNF168, ∆MLH1, ∆MSH2, ∆MSH6, ∆PMS1 and ∆PMS2 produced marked mutational signatures indicative of them being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-2′-deoxyguanosine elimination is sequence context specific while uracil clearance is sequence context independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C > A transversions) and differential misincorporation by replicative polymerases (T > C and C > T transitions), and we propose a reverse template slippage model for T > A transversions. ∆MLH1, ∆MSH6 and ∆MSH2 signatures were similar to each other but distinct from ∆PMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 whole-genome-sequenced cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies.
The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells
Brina, Daniela; Ponzoni, Adele; Troiani, Martina; et al. (2023)
Nature Cancer
Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs. Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.
MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation
Cangkrama, Michael; Liu, Huan; Wu, Xiaoyu; et al. (2025)
Nature Cancer
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies.

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