Autocrine Activation of MAPK-Signaling Mediates Intrinsic Tolerance to Androgen Deprivation in LY6D Prostate Cancer Cells

Steiner, Ivana; Flores-Téllez, Teresita del N.J.; Mével, Renaud; Ali, Amin; Wang, Pengbo; Schofield, Pietà; Forsythe, Nicholas; Ashton, Garry; Taylor, Catherine; Mills, Ian G.; Oliveira, Pedro H.; McDade, Simon S.; Zeiss, Dietmar; Choudhury, Ananya; Lacaud, Georges; Baena, Esther

doi:10.2139/ssrn.3966640

Cited by 1 publication

(1 citation statement)

References 87 publications

(122 reference statements)

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“…Finally, ~ 70% of the genomic loci occupied by both transcription factors in mPrOs EV (DE+PE; FA0 n=250+31) were exclusively occupied by Foxa1 in mPrOs Foxa1 (DE+PE; F1b n=179+23) (Figure 3C-F). In the group of loci occupied by Ar in mPrOs EV and in which Foxa1 replaced Ar in mPrOs Foxa1 (F1a (r)), we found the distal elements (DE) of the progenitor markers Wfdc2, Krt19, Sox5, Fgf1 and Runx2 and the luminalassociated genes Krt8, Cldn4 and Steap4 (8,9,11,13,18,36), which result upregulated upon ATRA treatment (Figure 3C-F, Supplementary Figure S4C and Supplementary Table S3).…”

Section: Foxa1 Occupies Enhancers and Promoters Of Key Luminal Progen...mentioning

confidence: 99%

Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Felice,

Alaimo,

Bressan

et al. 2024

Preprint

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Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in directing body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling promotes cell lineage identity in different tissues is often missing. Here, leveraging prostate organoid technology, we demonstrated that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and ultimately, proper specification of the prostatic lumen. Mechanistically, RA-dependent RARγ activation promotes the expression of the pioneer factor Foxa1, which synergizes with the androgen pathway for proper luminal expansion, cytoarchitecture and function. FOXA1 nucleotide variants are common in human prostate and breast cancers and considered driver mutations, though their pathogenic mechanism is incompletely understood. Combining functional genetics experiments with structural modeling of FOXA1 folding and chromatin binding analyses, we discovered that FOXA1F254E255 is a loss-of-function mutation leading to compromised transcriptional function and lack of luminal fate commitment of prostate progenitors. Overall, we define RA as a crucial instructive signal for glandular identity in adult prostate progenitors. We propose deregulation of vitamin A metabolism as a risk factor for benign and malignant prostate disease, and identified cancer associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

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Section: Foxa1 Occupies Enhancers and Promoters Of Key Luminal Progen...mentioning

confidence: 99%

Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Felice,

Alaimo,

Bressan

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Autocrine Activation of MAPK-Signaling Mediates Intrinsic Tolerance to Androgen Deprivation in LY6D Prostate Cancer Cells

Cited by 1 publication

References 87 publications

Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

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