The microenvironment influences cancer transcriptional state and drives drug response.

  • Major Finding: The microenvironment influences cancer transcriptional state and drives drug response.

  • Concept: Comparison of metastatic biopsies and matched organoids determined environmental control of transcriptional heterogeneity.

  • Impact: The developed framework provides insight into drivers of cancer cell state and their impact on drug response.


Despite the existence of single-cell RNA sequencing (scRNA-seq)–derived transcriptional maps of cancer, the influence cell-intrinsic and cell-extrinsic factors have on cancer cell state remains to be fully elucidated. Raghavan, Winter, Navia, Williams, and colleagues developed and utilized a high-resolution platform to profile metastatic tissue and matched organoid models from patients with pancreatic cancer using scRNA-seq to show that, although genomic alterations were conserved between tumors and cancer models, the same was not always true for RNA signatures. The programs derived from the single-cell cohort of metastatic disease samples were denoted as single-cell basal (scBasal) or single-cell classical (scClassical). These states were not mutually exclusive and could be coexpressed by individual cells, leading to a third subset, the intermediate coexpressor (IC) state, which demonstrated a distinct 115-gene signature. Investigation into separation between biopsy and corresponding organoid transcriptional profiles indicated divergence with robust loss of the scBasal gene signature in some organoids, and to a lesser extent the IC program, while the scClassical signature remained relatively preserved, suggesting that microenvironmental factors could induce the observed gene expression program changes. To investigate how this selection and plasticity occurs, organoids were grown in minimal media lacking serum and mitogens, which caused a shift toward a more scBasal or IC state, while organoids in typical growth-stimulating media exhibited an scClassical expression pattern. However, this did not fully recapitulate the polarization observed in vivo, supporting the critical role of factors within the tumor microenvironment (TME) in dictating cell state. Furthermore, TME composition was determined to be more diverse in scClassical or IC expression patterns, while scBasal-classified tumors had a more homogenous TME, with differentially expressed secreted factors being responsible for driving malignant cell state. Shifts in cancer cell state in response to TME signals were also able to alter drug response. This study provides insight into cancer cell transcriptional states as well as their plasticity and functional significance, which could eventually support targeting cell state to improve therapeutic response.

Raghavan S, Winter PS, Navia AW, Williams HL, DenAdel A, Lowder KE, et al. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell 2021;184:6119–37.e26.

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