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Extracellular matrix regulates lineage plasticity in prostate cancer through YAP/TEAD

Teng HaniD, Zhen SuniD, Matthew LangeiD, Y Zoe Cho, Patrick D. McGillivrayiD, Maren BüttneriD, Nathaniel R. KastaniD, Subhiksha NandakumariD, HuiYong ZhaoiD, Eralda SalatajiD, Sanyukta Oak, Linda E. FongiD, Wenfei Kang, Ning FaniD, Francesca MazzoniiD, Radhika A. PateliD, Jimmy Zhao, Nazifa SalsabeeliD, Harmanpreet KauriD, Ninghui MaoiD, Qing ChangiD, Eric RosiekiD, Eric Chan, Murray J. TippingiD, Nikolaus SchultziD, , Charles L. SawyersiD

Abstract

Treatment-related neuroendocrine prostate cancer (NEPC) is an increasingly frequent mechanism of resistance to androgen receptor pathway inhibitor (ARPI) therapy in prostate adenocarcinoma (PRAD). This lineage transition is dependent on upregulation of the NE-specifying transcription factor ASCL1, typically in a genetic background of RB1 and TP53 loss. Here we identify extracellular matrix-integrin-YAP1/TEAD signaling as a critical brake on NEPC lineage transition. Deletion of Itgb1, the shared B1 subunit required for collagen and laminin-mediated integrin activation, is sufficient to induce ASCL1 and NE lineage gene expression, by activating LATS1/2 kinases with subsequent inactivation of YAP1/TEAD signaling. Conversely, restoration of YAP1/TEAD signaling by pharmacological LATS1/2 inhibition, or by expression of constitutively active YAP1/TAZ mutants, prevents or reverts NEPC lineage transition. NOTCH and AR cooperate with YAP/TEAD to repress ASCL1, such that combined inhibition leads to complete reprograming of PRAD into NEPC in vitro, providing a dynamic platform to dissect the molecular events responsible for lineage transition over time. We find that lineage transition is accompanied by a redistribution of FOXA1 and TEAD cistromes from PRAD to NEPC-specific enhancers and requires the pioneering activity of FOXA1. Thus, extracellular matrix/integrin signaling in the PRAD tumor microenvironment restrains NE lineage plasticity, highlighting a potential path for pharmacological inhibitors in modulating treatment-induced lineage change.

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Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (23 Aug 2026) · CC BY 4.0

Loss of extracellular matrix-integrin signaling switches off YAP/TEAD and lets prostate adenocarcinoma organoids turn neuroendocrine; LATS inhibition reverses it, and combined YAP, NOTCH and AR inhibition fully reprograms them.

Loss of RB1 and TP53 is not sufficient for neuroendocrine transition, and Rb1/Trp53-deficient organoids stay adenocarcinoma in culture, which points to tumor microenvironment cues. The paper names matrix-integrin-YAP/TEAD signaling as one such brake and builds an in vitro platform that reproduces the full transition.

Key results

  1. SuggestedStromal cells and matrix are depleted in neuroendocrine regions of mouse tumors and in NEPC-high human Visium spots. In bulk metastatic CRPC the stromal difference did not reach significance.

    Visium: 44.7% of PRAD-high spots (33,015/73,827) vs 20.7% of NEPC-high spots (771/3,719) had high stroma (chi-squared p=5.17×10^-182). SU2C bulk (n=266): median stromal theta 0.089 vs 0.142, p=0.095. · Relative depletion of stroma and extracellular…; Analysis of spatial co-localization of tumor and…; Bulk RNA-seq deconvolution; Figure legends

  2. ShownRemoving Matrigel or deleting Itgb1 induces Ascl1 and NE genes in TKOM organoids. Blocking YAP/TEAD does the same, and constitutively active YAP or TAZ prevents it.

    Ascl1 was the top upregulated gene in suspension RNA-seq. IAG933 gave ~300-fold Ascl1 vs ~30-fold for dasatinib; Yap1/Wwtr1 co-deletion gave >100-fold. Replating into Matrigel did not reverse NE marker expression at 10 or 30 days. · ECM withdrawal initiates PRAD to NEPC lineage…; ECM-integrin signaling maintains PRAD lineage; YAP1/TAZ/TEAD suppresses Ascl1 induction and NE…

  3. SuggestedRestoring YAP/TEAD activity reverses an established NE state. LATS1/2 inhibition (TRULI) did this in mouse tumoroids and patient-derived organoids, and inducible active YAP1 did it in transplanted tumors.

    NEPC tumoroids lost ASCL1, INSM1 and CHGA after 4 days of TRULI. In patient-derived organoids ASCL1-positive cells fell from >60% to <5%. Three days of YAP1 5SA induction reversed ASCL1, FOXA2 and INSM1 in subcutaneous tumors (n=8 mice per group). · LATS inhibition impairs acquisition and…

  4. ShownCombined YAP, NOTCH and AR inhibition (COMBO) reprograms adenocarcinoma organoids into an NEPC-like state over 42 days. The NE program switches on regardless of RB status, but only RB1-null cells keep proliferating.

    On a 0 (PRAD) to 1 (NEPC) transition score, 42-day COMBO approached the three NEPC tumoroids; 8-day YAPi/NOTCHi and COMBO scored 0.4-0.6. The Ascl1 reporter was on in ~70% of TKO cells vs ~20% of PtP cells. · Cooperativity of YAP1/TEAD, NOTCH and AR…; Complete reconstitution of PRAD to NEPC lineage…; PRAD-to-NEPC transition score analysis

  5. ShownFOXA1 is required early in the transition. FOXA1 and TEAD1 binding both relocate from PRAD to NEPC enhancers, and Foxa1 deletion diminishes the opening of NE-specific chromatin and abrogates Ascl1 induction.

    Foxa1 deletion diminished the ATAC-seq increase at NE loci after 4 days, abrogated Ascl1 induction and blocked new TEAD peaks. Pan-Tead knockdown cut Ascl1 induction by ~50%. Foxa2 or Insm1 deletion had no effect on early Ascl1. · FOXA1 is essential for the PRAD to NEPC lineage…

Methods, data and reproducibility

Mouse prostate organoids carrying combinations of Rb1, Trp53, Pten loss and cMyc were perturbed by Matrigel withdrawal, CRISPR knockouts, inhibitors and active YAP/TAZ alleles. Readouts were qRT-PCR, bulk RNA-seq, multiome, ATAC-seq and CUT&RUN, with transplants and human specimens as support.

  • Mouse prostate organoid lines (TKO, TKOM, RPM, PtP, WT), tumoroids and orthotopic or subcutaneous transplants · mouse · n = qRT-PCR typically n=3; 8 or 12 mice per group in YAP1 5SA transplants · GSE343498, GSE343500, GSE343502, GSE343504
  • SU2C/PCF metastatic CRPC bulk RNA-seq, deconvolved with BayesPrism · human · n = 266; Fig 1B legend lists 73 NE-positive, 210 CRPC-adeno (sum > 266) · prad_su2c_2019 (cBioPortal)
  • Visium spatial transcriptomics of prostate cancer (Kiviaho et al. 2024) · human · n = 48 slides; 112,080 spots after QC · GSE278936
  • Single-cell reference atlas of prostate tumors (Zaidi et al. 2024) for deconvolution · human · n = 119,083 cells · GSE264573
  • Single-cell multiome (RNA + ATAC) of TKOM organoids in Matrigel or suspension (2 and 20 days) · mouse · n = 23,134 cells, 147,895 peaks after QC
  • Patient-derived organoids from NEPC (MSKPCA14, MSKPCA10) · human · n = n=3 to 4 replicates per assay
  • Metastatic CRPC FFPE specimens with mixed PRAD/NEPC histology (rapid autopsy) · human · n = 3 patients
Methods & tools
BayesPrism (pybayesprism), Scanpy, cellranger-arc, DESeq2, MACS2, HOMER, GSVA/ssGSEA, CRISPR-Cas9 RNP editing, CUT&RUN, IAG933 (YAP/TEAD inhibitor), TRULI (LATS1/2 inhibitor), deepTools
Reagents & environment
cellranger-arc v2.0.2, Scanpy v1.10.3, Python v3.10.15, R v4.3.2, DESeq2 v1.34.0, HOMER v4.11 (multiome) and v4.5 (peaks), deepTools v3.3.0.
Reproducibility gaps
No code repository is stated. GEO accessions are given without URLs; sgRNA and antibody details are in supplementary tables.
Limitations (5)
  • Comparing mouse primary prostate tumors with human metastatic CRPC specimens has limitations. · stated by the authors
  • LATS inhibitors could not be tested in mice because of rapid in vivo clearance and fast recovery of pYAP, so a genetic YAP1 5SA allele was used instead. · stated by the authors
  • Reversal of the NE state was shown only at early stages of the transition. · stated by the authors
  • TEAD1 knockdown was incomplete, with residual TEAD detected by a pan-TEAD antibody. · stated by the authors
  • Most causal evidence comes from engineered mouse organoids. Human support is correlative (three patient specimens, patient-derived organoids, cohort scores), and the bulk stromal difference was not significant. · noted in this summary

Who should read:Read this if you study lineage plasticity or treatment resistance in prostate cancer and want a tractable organoid system and a mechanism linking matrix, YAP/TEAD, NOTCH, AR and FOXA1.

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