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Resistance to endocrine treatment occurs in ~30% of ER + breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER + /HER2 − patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER + /HER2 − breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL - cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER + /HER2 − patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER + /HER2 − breast cancer patients. Resistance to endocrine treatment in ER+/HER2- breast cancer patients remains a significant clinical problem. Here, the authors demonstrate that loss of the MutL mismatch repair complex can serve as a first-in-class predictive biomarker for combinatorial inhibition of HER2 to overcome the emergence of endocrine treatment resistance.

Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA and our findings demonstrate that AOX1 is epigenetically silenced during BLCA progression by the methyltransferase activity of EZH2. Knockdown (KD) of AOX1 in normal bladder epithelial cells re-wires the tryptophan-kynurenine pathway resulting in elevated NADP levels which may increase metabolic flux through the pentose phosphate (PPP) pathway, enabling increased nucleotide synthesis, and promoting cell invasion. Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD. Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts. Further gain and loss of AOX1 confirm the EZH2-dependent activation, metabolic deregulation, and tumor growth in BLCA. Our findings highlight the therapeutic potential of AOX1 and provide a basis for the development of prognostic markers for advanced BLCA.

After publication of this Article, the Authors noticed errors in some of the Figures. In Figures 2e, 2f–g, 4a, 4j, 5a and 6b, unmatched β-actin was inadvertently used as loading control for the immunoblots. These have been corrected using repeat data from a similar set of samples and the revised Figures containing matched β-actin and their respective quantification data are included below. In Figure 7a, the same image was inadvertently used to represent tumors 3 and 5 in the control group. This error has been corrected using original images of tumors 3 and 5 in the control group. Additional corrections have been made in the Article and Figure legends to enhance the clarity of the description. NAD was replaced by NADP. NAD/NADP was replaced by NADP/NADPH. The description of the antibody source and dilution for the antigens PFKFB4 (Abcam, 1:1000), G6PD, and HK1 (Cell Signaling, 1:1,000) have been included in the Methods section for Western Blot. The legend for Figure 4e and 4j has been updated. The HTML and PDF versions of this Article have been corrected. The scientific conclusions of this paper have not been affected.

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype, comprising 10-15% of breast cancers. Immune checkpoint inhibitors (ICIs), especially when combined with radiation therapy (RT), have shown promise, and tumor microenvironment (TME) immune cell presence correlates with ICI response. While distinct TME immune phenotypes (R1, R2, and non-responders) have been characterized, the overarching contribution of systemic immunity to these diverse treatment responses is not fully understood. By investigating the role of these broader immune components in treatment outcomes, this study aims to identify accurate predictive biomarkers.MethodsWe collected baseline and on treatment PBMC samples (n=54) from patients enrolled in NCT03366844, and performed single cell RNA sequencing(scRNAseq), single cell TCR/BCR sequencing (scTCR/BCR seq) and CITE sequencing on CD45+ cells, which was combined with tumor data of each patient.ResultsBy analyzing the scRNA and scTCR/BCR data and by tracking each clonotype, we discovered that T cells in PBMCs provides a reflection of ongoing tumor responses (1018 clonotypes). We observed that with treatment, a PBMC enriched cell type Temra CD8 T was key contributor of systemic immunity as they were able to transition to clinically relevant CD8 T cells in the tumor and contribute to response. Interestingly these systemic immune responses were different between the response groups i.e. In R1 responders we observed that the response was driven by T cells in local TME, whereas in R2 responders the response was derived from Temra CD8. Our investigation also uncovered metabolic differences in Temra CD8 T cells from R2 responders compared to non-responders.ConclusionsImportantly, by integrating analyses of both tumor and peripheral blood mononuclear cells (PBMCs), we were able to detect systemic immunity within PBMCs at baseline and were able to discover the involvement of Temra T cells in the differentiation process of tumor-reactive T cells. This latter finding is particularly significant as R2 responders are characterized by an immune-excluded phenotype, suggesting a more complex interplay of systemic immunity than previously assumed.

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations are consistently associated with poor prognosis, whereas ATM mutations correlate with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters are identified and refined into three prognostic groups: high-risk ( TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk ( ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis reveals enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFNα, TNFα) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrates enrichment of CD4⁺ T cells with high expression of exhaustion markers and a dominant population of myeloid cells skewed toward an M2-like phenotype. Spatially, TP53 -perturbed MCLs are immune-infiltrated yet exhausted, while ATM -perturbed cases remain immune-cold with dense tumors. Functional analysis shows that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53 -perturbed MCL. Mantle cell lymphoma (MCL) is a form of B-cell non-Hodgkin lymphoma with a high degree of genetic and clinical heterogeneity. Here, using a multi-omics approach, the authors investigate genetic alterations in association with the tumour microenvironment to identify potential therapeutic vulnerabilities.

Estrogen receptor positive (ER+) breast cancer is a leading cause of cancer-related death globally. Resistance to standard of care endocrine treatment occurs in at least 30% of ER+ breast cancer patients resulting in ~40,000 deaths every year in the US alone. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance of ER+ breast cancer that is HER2- at diagnosis1,2. However, clinical trials of pan-HER inhibitors in ER+/HER2- patients have disappointed, likely due to a lack of predictive biomarkers3-6. Here we demonstrate that loss of MLH1, a principal mismatch repair gene, causally activates HER2 in ER+/HER2- breast cancer upon endocrine treatment. Additionally, we show that HER2 activation is indispensable for endocrine treatment resistant growth of MLH1- cells in vitro and in vivo. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment in multiple experimental models including patient-derived xenograft tumors. Patient data from multiple clinical datasets (TCGA, METABRIC, Alliance (Z1031) and E-GEOD-28826) supports an association between MLH1 loss, HER2 upregulation, and sensitivity to trastuzumab in endocrine treatment-resistant ER+/HER2- patients. These results provide strong rationale that MLH1 could serve as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine drugs and HER inhibitors in endocrine treatment-resistant ER+/HER2- breast cancer patients. Implications of this study extend beyond breast cancer to Lynch Syndrome cancers. Defective mismatch repair activates HER2 in HER2-negative breast cancer cells and renders them susceptible to HER2 inhibitors.

We designed a study investigating the cardioprotective role of sleep apnea (SA) in patients with acute myocardial infarction (AMI), focusing on its association with infarct size and coronary collateral circulation. We recruited adults with AMI, who underwent Level-III SA testing during hospitalization. Delayed-enhancement cardiac magnetic resonance (CMR) imaging was performed to quantify AMI size (percent-infarcted myocardium). Rentrop Score quantified coronary collateralization (scores 0-3, higher scores indicating augmented collaterals). Group differences in Rentrop grade and infarct size were compared using the Wilcoxon Rank-Sum test and Fisher's Exact test as appropriate, with a significance threshold set at p <0.05. Among 33 adults, mean age was 54.4±11.5 and mean BMI was 28.4±5.9. 8 patients (24%) had no SA, and 25 (76%) had SA (mild n=10, moderate n=8, severe n=7). 66% (n=22) underwent CMR, and all patients had Rentrop scores. Median infarct size in the no-SA group was 22% versus 28% in the SA group (p=0.79). While we did not find statistically significant differences, moderate SA had a trend toward a smaller infarct size (median 15.5%; IQR 9.23) compared to the other groups (no SA [22.0%; 16.8,31.8], mild SA [27%; 23.8,32.5], and severe SA [34%; 31.53], p=0.12). A higher proportion of moderate SA patients had a Rentrop grade >0, with a trend toward significance (moderate SA versus other groups: 62.5% versus 28%, p=0.08). Our study did not find statistically significant differences in cardiac infarct size and the presence of coronary collaterals by sleep apnea severity among patients with AMI. However, our results are hypothesis-generating, and suggest that moderate SA may potentially offer cardioprotective benefits through enhanced coronary collaterals. These insights call for future research to explore the heterogeneity in ischemic preconditioning by SA severity and hypoxic burden to guide tailored clinical strategies for SA management in patients with AMI.