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Lung Cancer Therapy Leads to Transcriptional Changes, Single-Cell Study Shows

NEW YORK – Targeted therapies lead to transcriptional changes in lung cancer cells that could be harnessed to improve patient outcomes, a new single-cell study has found.

A University of California, San Francisco-led team collected samples from metastatic lung cancer patients before and during targeted therapy for single-cell RNA sequencing-based analyses. Lung cancer, which affects more than 228,000 people in the US each year according to the National Cancer Institute, is highly heterogeneous, which could contribute to adaptations that limit the efficacy of personalized therapies.

By generating transcriptomic profiles for more than 20,000 cancer and tumor microenvironmental cells, the researchers began to uncover oncogenes within the tumors beyond the ones targeted by therapeutics. They also uncovered signatures common to cells representing residual disease and progressive disease samples. 

As they reported Thursday in the journal Cell, the researchers suggested the findings could be applied to improve therapeutic responses.

"The data provide a foundation to develop strategies for the elimination or neutralization of [residual disease] to induce more durable responses for patients with advanced-stage NSCLCs and potentially other solid malignancies across different therapeutic modalities," UCSF's Trever Bivona and colleagues wrote in their paper.

Using single-cell RNA sequencing, the researchers profiled 49 samples from 30 patients, encompassing 45 lung adenocarcinomas, one squamous cell carcinoma, and three tumor-adjacent tissue samples. Some samples were collected prior to treatment, while others were collected during treatment or upon disease progression. In all, the researchers generated gene-expression profiles for 23,261 cells.

For about half of the biopsy samples that included cancer cells, the researchers could detect the clinically known oncogenic driver genes. But in a portion of those samples, they also uncovered oncogenic alterations that were not identified in the clinically performed bulk tumor testing. This suggests that bulk testing might underestimate tumor heterogeneity, and could account for the rarity of complete responses, they noted.

The researchers compared the transcription profiles of cells from residual disease to those collected prior to treatment and, in general, found residual disease cells expressed lower levels of proliferative markers.

At the same time, an alveolar cell signature increased in expression in residual disease. Within the TCGA lung adenocarcinoma dataset, this alveolar cell signature was associated with improved patient outcomes. The signature indicates that treatment induces a transition to a primitive cell state, and is linked to the WNT/beta-catenin pathway, which is involved in injury repair, and is potentially targetable with therapeutics, the researchers noted.

The researchers likewise compared the gene expression profiles of cells from progressive disease samples to treatment-naive cell samples to find more than 900 upregulated genes. This set included genes involved in the kynurenine pathways as well as genes involved in oncogenesis and inflammation pathways.

By tracing gene expression changes from residual to progressive disease, the researchers uncovered more than 2,000 genes whose expression differs between the two states. Overall, residual disease cells overexpressed genes associated with the alveolar cell signature as well as cell growth, differentiation cell motility, and tumor suppression, while progressive disease cells overexpressed genes linked to invasion, cell-to-cell communication, differentiation, and immune modulation.

The researchers similarly noted changes in the tumor microenvironment as treatment progressed that reflected a more pro-inflammatory stage during residual disease, as compared to before treatment or upon disease progression. 

Overall, the researchers noted that their findings suggest treatments could be applied to take advantage of these various cell states. "If deployed at the appropriate time, treatments that target liabilities of a specific cell state or prevent further adaptation may help improve patient survival by constraining continued tumor evolution toward complete drug resistance," the researchers wrote in their paper.