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The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer
Michalina Janiszewska, … , Franziska Michor, Kornelia Polyak
Michalina Janiszewska, … , Franziska Michor, Kornelia Polyak
Published April 22, 2021
Citation Information: JCI Insight. 2021;6(11):e147617. https://doi.org/10.1172/jci.insight.147617.
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Research Article Oncology

The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer

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Abstract

Despite the availability of multiple human epidermal growth factor receptor 2–targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1–positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.

Authors

Michalina Janiszewska, Shayna Stein, Otto Metzger Filho, Jennifer Eng, Natalie L. Kingston, Nicholas W. Harper, Inga H. Rye, Maša Alečković, Anne Trinh, Katherine C. Murphy, Elisabetta Marangoni, Simona Cristea, Benjamin Oakes, Eric P. Winer, Ian E. Krop, Hege G. Russnes, Paul T. Spellman, Elmar Bucher, Zhi Hu, Koei Chin, Joe W. Gray, Franziska Michor, Kornelia Polyak

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Figure 6

Stromal cell analysis by scRNA-Seq reveals distinct cell types contributing to differential drug response.

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Stromal cell analysis by scRNA-Seq reveals distinct cell types contribut...
(A) Combined analysis of stromal cells from n = 2 samples per each PDX and each condition (total 24 samples, average cell number per sample = 2169). UMAP plots colored by cluster (left panel), PDX (middle panel), and treatment (right panel). (B) Cell distribution among clusters based on PDX from which they were derived. (C) Analysis of stromal cells from PDX1. UMAP plots colored by cluster (left) and treatment (right). AL, alveolar luminal cells; pDC, plasmacytoid dendritic cells; FRCs, fibroblastic reticular cells. (D) Stromal cells from PDX1 distribution among clusters based on treatment. (E) Expression of Wfdc18 in different clusters of PDX1 stromal cells (log-normalized expression values). Unpaired 2-tailed Student’s t tests P value of comparison of cluster 8 to each of the other clusters is shown. (F) MetaCore GO Processes upregulated in AL cluster. (G) Analysis of stromal cells from PDX2. UMAP plots colored by cluster (left) and treatment (right). (H) Stromal cells from PDX2 distribution among clusters based on treatment. (I) GO Processes upregulated in 3 PDX2 macrophage clusters 0, 1, and 4. (J) Expression of Lyve1 in different clusters of PDX1 stromal cells (log-normalized expression values). Unpaired 2-tailed Student’s t tests P value of comparison of cluster 4 with each of the other clusters. (K) GO processes upregulated in 2 PDX2 FRC clusters 5 and 8. (L) GO processes upregulated in cluster 5 compared with cluster 8. (M) GO processes upregulated in cluster 8 compared with cluster 5. (B, D, and H) Red color, lower than expected frequency; blue, higher than expected. P value of χ2 test is shown.

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