Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer
Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley
Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley
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Research Article Cell biology Oncology

Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer

Abstract

Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identified a paracrine mechanism in which CAF-secreted asporin (ASPN) activated ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data support that ASPN bound directly to the ligand binding domain of human epidermal growth factor 3 (HER3) and induced HER2/HER3 heterodimerization and activation of the PI3K, MAPK, and calcium pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Clinically, ASPN was detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.

Authors

Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley

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Figure 8

Stromal expression of ASPN occurs in the TME of HER2/HER3-expressing metastatic prostate cancer.

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Stromal expression of ASPN occurs in the TME of HER2/HER3-expressing met...
(A) Representative images of distant prostate cancer metastases analyzed by dual IHC for HER2 and RNAscope for ASPN (n = 33), IHC for HER3 (n = 33), and RNAscope for NRG1 (n = 31). The black arrow highlights an NRG1-positive cell. (B–D) Quantification of HER2 expression in cancer cells by IHC as determined by H-Score (0, 1+, 2+, 3+ intensity × percent positive) and compared by mHSPC (n = 11) versus mCRPC (n = 22) (B), bone (n = 11) versus soft tissue (n = 22) (C), and all sites (n = 33) (D). (E–G) Quantification of HER3 expression in cancer cells by IHC as determined by H-Score (0, 1+, 2+, 3+ intensity × percent positive) and compared by mHSPC versus mCRPC (E), bone versus soft tissue (F), and all sites (G). (H–J) Quantification of ASPN (n = 33) and NRG1 (n = 31) expression in metastatic prostate cancer stroma by RNAscope as determined by H-Score (0, 1+, 2+, 3+ intensity × percent positive) and compared by mHSPC (n = 11) versus mCRPC (n = 22 for ASPN and n = 20 for NRG1) (H), bone (n = 11) versus soft tissue (n = 22 for ASPN and n = 20 for NRG1) (I), and all sites (n = 33 for ASPN and n = 31 for NRG1) (J). (K and L) Percentage of samples that expressed HER2, HER3, and ASPN by mHSPC versus mCRPC (K) and bone versus soft tissue (L). (M and N) Quantification of NRG1 (n = 31) expression in cancer cells by RNAscope as determined by H-Score (0, 1+, 2+, 3+ intensity × percent positive) and compared by mHSPC (n = 11) versus mCRPC (n = 20) (M) and bone (n = 11) versus soft tissue (n = 20) (N). Graphs shown as mean ± SEM and analyzed by Student’s 2-tailed t test (B, C, E, F, M, and N) or 1-way ANOVA with Tukey’s post hoc analysis (H and I). Graphs are shown as percent and analyzed by Fisher’s exact test (K and L); *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.