In This Issue

Although several large-scale genomic studies of pan-cancer cohorts have revealed essential molecular aberrations, most patients analyzed are of European ancestry. Park and colleagues explored the genomes of 4,028 East Asian patients across 24 tumor types as part of the K-MASTER initiative. Profound levels of genomic diversity existed at both pan-cancer and individual tumor levels between patients of different ethnic origins. For example, mutations in key chromatin remodeling genes were observed only in cholangiocarcinoma patients of European ancestry, whereas East Asian patients were marked by recurrent KRAS and TP53 aberrations. Understanding the unique features of patients with East Asian ancestry can facilitate personalized therapy in this population.

See article, p. 938.

DNA mutations are acquired in every cell division since early in embryogenesis, but their contribution to the development of sporadic cancers is unknown. Through the analysis of tumor/normal paired sequencing data, Pareja, Ptashkin, Brown, and colleagues identified individuals harboring mosaic variants in cancer susceptibility genes (CSG) whose distribution across normal tissues of different developmental lineages indicated their early embryologic origin. Tumors displayed genetic and phenotypic features consistent with somatic inactivation of the respective CSG harboring early mosaic variants, indicating their cancer causative role. Early mosaic variants affecting CSGs may explain cancer development risk, and their detection may guide therapeutic and prophylactic decisions.

See article, p. 949.

Protection from SARS-CoV-2 infection has been measured by antibody levels, but an understanding of the protection mediated by T cells remains necessary. Fahrner, Lahmar, Goubet, Haddad, and colleagues assessed how the polarity and repertoire of T-cell responses correlated with susceptibility to infection in both cancer-bearing and healthy individuals during subsequent waves of the pandemic. Higher susceptibility to SARS-CoV-2 infection was associated with a deficit in the Th1/Tc1 response of memory T cells specific to the receptor binding domain of the spike protein, emphasizing a need to both measure T-cell responses to determine protection and develop vaccines that induce antiviral T-cell immunity.

See article, p. 958.

Platinum-based chemotherapy is the backbone of treatment for advanced gastric cancer; however, only ∼50% of patients respond, and the effects on the tumor immune microenvironment are unknown. Kim, An, Lee, Mehta, and colleagues used single-cell RNA sequencing as well as whole-transcriptome and bulk RNA analyses from paired pre- and on-treatment tissue samples during frontline chemotherapy to study microenvironmental remodeling. Responding patients demonstrated distinct features including natural killer cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Increased Wnt-pathway signaling, limited T-cell infiltration, and loss of dendritic cell populations were observed in nonresponders, suggesting potential therapeutic opportunities to improve response.

See article, p. 984.

Brain metastasis is a severe complication in 40% of patients with EGFR-mutant lung cancer and is a common site of relapse after EGFR tyrosine kinase inhibitor (TKI) treatment. The EGFR TKI osimertinib reduces the risk of central nervous system progression; however, cells still escape and initiate metastatic relapse. Biswas and colleagues present long-term in vivo treatment models that recapitulate the osimertinib response and relapse observed in patients with EGFR-mutant lung cancer. Using these models, a novel intracellular S100A9–ALDH1A1–retinoic acid signaling pathway that drives lethal brain relapse was identified, which can be targeted by pan-retinoic acid receptor (RAR) antagonists to prevent cancer progression and prolong patient survival.

See article, p. 1002.

Drug-tolerant persisters (DTP) are implicated in resistance to tyrosine kinase inhibitors (TKI) in several malignancies, but they have not been well characterized in HER2⁺ breast cancer. Chang, Jen, and colleagues discovered that HER2 TKIs yield DTPs with two distinct transcriptional states. Moreover, lentiviral barcoding and single-cell RNA sequencing reveal that HER2⁺ breast cancer cells cycle stochastically through a “pre-DTP” state, characterized by enrichment for G₀ diapause and senescence genes. Upon HER2 TKI exposure, pre-DTPs preferentially give rise to DTPs. Cells with pre-DTP expression features are also present in HER2⁺ tumors and are associated with poor TKI response in neoadjuvant trials.

See article, p. 1022.

Oncogene amplifications provide resistance to MAPK inhibitors (MAPKi), and a more complete understanding of the mechanisms underlying amplicon genomic structures and dynamics could improve these therapies. Song and colleagues developed a melanoma model of dual-MAPKi resistance with two modes of BRAF^V600 amplification: extrachromosomal DNA (ecDNA)/double-minutes and intrachromosomal homo­genously staining regions (HSR). This model reveals that both modes display drug dose–responsive plasticity under various MAPKi dose challenges. The plasticity of HSR shortening aids in the expansion of cells recovering from drug addiction and involves structural loss of BRAF amplicon repeats. BRAF amplification–mediated dual MAPKi–resistant cells were more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in melanoma.

See article, p. 1046.

The polyphenol castalagin, isolated from the Amazonian berry camu-camu (Myrciaria dubia), was identified by Messaoudene and colleagues to demonstrate anticancer activity. Oral supplementation of castalagin in mice was associated with an enrichment of Ruminococcus and Alistipes as well as an upregulation of CD8⁺ T-cell cytotoxicity in the tumor microenvironment, leading to a stronger anti–PD-1 response. In murine models, fecal microbiome transplantation using immune checkpoint inhibitor (ICI) nonresponder patient feces followed by castalagin supplementation restored anti–PD-1 activity, supporting a strong biological rationale to test castalagin as an adjuvant to ICI in patients with cancer.

See article, p. 1070.

Tumor sequencing initiatives have amassed bulk DNA and RNA data from a mixture of cell types in tumor samples, but cell-type information is still limited. Wang, Patkar, and colleagues developed a new method, called CODEFACS, to estimate the mean expression of each gene in each cell type and each sample. CODEFACS incorporates confidence estimates to demonstrate the reliability of the gene expression prediction. Furthermore, an additional method, termed LIRICS, was developed to identify cell-type–specific ligand–receptor interactions that can predict responses to immunotherapy based upon deconvolved gene expression data and prior immunologic knowledge.

See article, p. 1088.

Acute myeloid leukemia (AML) remains recalcitrant to treatments due to the emergence of resistant clones, but signals triggered by cells in the bone marrow (BM) microenvironment can be pharmacologically harnessed to overcome therapy resistance. Galán-Díez and colleagues found that AML progression requires expression of serotonin receptor-1b (HTR1B) in osteoblasts and is driven by AML secretion of kynurenine. Kynurenine acts as a HTR1B ligand, triggering secretion of acute-phase protein serum amyloid A (SAA), which increases expression of IDO1, the enzyme catalyzing kynurenine synthesis in leukemia cells, perpetuating AML progression with inhibition of this pathway hampering AML growth.

See article, p. 1106.

Whether intestinal dysbiosis is a consequence of tumorigenesis and how it can control tumor progression remain open questions. Yonekura, Terrisse, Alves Costa Silva, and colleagues showed that in 50% of cases, transplantable extraintestinal malignancies could induce beta-adrenergic receptor–dependent ileal mucosa atrophy, associated with transient crypt apoptosis, ectopic proliferation of enteroendocrine and tyrosine hydroxylase–positive cells, increased gut permeability, and sustained Clostridium species related–dysbiosis, culminating in cancer outgrowth. Vancomycin or propranolol could prevent cancer-associated stress ileopathy. Human malignancies are often accompanied with an ectopic proliferation of enteroendocrine cells and an overrepresentation of Enterocloster and Clostridium species.

See article, p. 1128.

NUP98 fusion oncoproteins (FO) drive hematopoietic transformation in high-risk pediatric leukemias. These FOs harbor a phase separation–prone disordered region from NUP98 juxtaposed to DNA- or chromatin-binding domains from their C-terminal fusion partners. Chandra, Michmerhuizen, Shirnekhi, Tripathi, and colleagues show that several NUP98 FOs undergo phase separation to form hundreds of nuclear puncta that promote leukemogenic gene expression and hematopoietic cell transformation. Phase separation is driven by multivalent protein interactions mediated by >30 phenylalanine-glycine motifs within the NUP98 region of the FOs and interactions of the C-terminal domains with DNA or chromatin, indicating that phase separation is critical for leukemogenesis.

See article, p. 1152.