Summary Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.

Purpose Gastric cancers (GC) may harbor a small subset of cells with cancer stem cell (CSC) properties including chemotherapy (CT) resistance. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here we examine the role of HH signaling in CD44(+) GC cells. Experimental Design GC cell lines, tumor xenografts, and patient tumors were examined. Results GC cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smo shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared to unselected cells, were also resistant to 5-fluorouracil and cisplatin CT, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial for advanced GC of CT with or without VIS were analyzed for CD44 expression. In the CT alone group, high CD44 expression was associated with decreased survival, while in the CT plus VIS group, high CD44 expression was associated with improved survival. Conclusions HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) GC cells, and HH inhibition can block CT resistance in CD44(+) cells. GC is a heterogeneous disease, and the strategy of combining CT with HH inhibition may only be effective in the subset with high CD44 levels.

Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 ϫ 10 5 ) were injected subcutaneously into the scruff of 6-to 8-wk-old male C57BL/6 mice (n ϭ 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/ wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) ϩ vehicle, 2) SED ϩ DOX, 3) EX ϩ vehicle, and 4) EX ϩ DOX. Tumor volume was attenuated in DOX and lowest in EX ϩ DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ␤-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOXinduced cardiotoxicity in a murine model of melanoma. neoplasm; drug therapy; cardiotoxicity; heart DOXORUBICIN (DOX) is an anthracycline with broad clinical application across the cancer spectrum as an effective antineoplastic agent (14, 30). However, progressive and dose-dependent early and late-onset cardiotoxicity limits the clinical efficacy of DOX (9). Acute cardiotoxicity is associated with arrhythmias and transient left ventricular (LV) dysfunction, whereas late-onset cardiomyopathy, which can occur up to 15 years after DOX administration, can manifest with overt LV dysfunction and heart failure (35). This is a significant clinical issue given cancer survivors already face a 15-fold increased rate of heart failure (27).There are numerous transcriptional and posttranslational pathophysiological mechanisms associated with DOX-induced cardiotoxicity, including increased generation of reactive oxygen species and lipid peroxidation, mitochondrial damage, DNA damage, reduction in protein synthesis, increased apoptosis, and alterations in ␤-adrenergic signaling and Ca 2ϩ handling (28). A recent study also showed that DOX caused nearly full extinction of competent cardiac progenitor cells. Subsequent intramyocardial injections of syngeneic cardiac progenitors rescued the heart from DOX-induced cardiotoxicity (7). These data suggest that a reduction in cardiomyocyte cell number...

No abstract

Introduction: Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multiinstitutional retrospective analysis aimed to compare outcomes in patients with EGFR-or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.Methods: Data were retrospectively collected from three academic institutions. Two treatment groups (CNS-penetrant TKI alone versus TKI þ CNS radiation therapy) were compared for both EGFR-and ALK-positive cohorts.

No abstract

No abstract