Abstract
SummaryLung 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.
Highlights
Heterogeneity is a property of many biological systems and diseases such as cancer
Samples were categorized into three separate time points (TN, residual disease (RD), or progressive disease (PD)) and further subcategorized by oncogenic driver (Figure 1C)
In agreement with our scRNA-seq findings, we found significantly increased membrane SUSD2 and significantly increased nuclear CTNNB1 (b-catenin) in the RD state compared with both TN and PD
Summary
Heterogeneity is a property of many biological systems and diseases such as cancer. Biological plasticity in cancer cells is one form of heterogeneity that allows for early adaptation to treatment and limits the success of precision approaches for cancer treatment (Xue et al, 2017; Yuan et al, 2019). In addition to cancercell intrinsic heterogeneity, cells within the tumor microenvironment (TME) further contribute to tumor heterogeneity in a cancer cell extrinsic manner. While these tumor compartments and tumor heterogeneity have been characterized in many cancer subtypes (Alexandrov et al, 2013; Brannon et al, 2014; Gerlinger et al, 2012; Hata et al, 2016; Lawrence et al, 2013; Lee et al, 2014; Vignot et al, 2015), our understanding of how these properties evolve and interact longitudinally in response to systemic treatment remains incomplete, in metastatic tumors.
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