Heme oxygenase-1 regulation of stemness and metastasis associated genes in prostate cancer-bone crosstalk

INES ACHINELLI; PABLO SANCHIS; AGUSTINA SABATER; NICOLAS ANSELMINO; SOFIA LAGE VICKERS; JUAN BIZZOTTO; GASTON PASCUAL; ROCIO SENIUK; JAVIER COTIGNOLA; ELBA VAZQUEZ; MARIA SOL RUIZ; GERALDINE GUERON; AYELEN TORO

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

Mortality in prostate cancer (PCa) is associated with bone metastasis and aggressive phenotypes promoted by prostate cancer stem cells (PCSCs). We have previously described that heme oxygenase-1 (HO-1) plays an antitumoral role in PCa. Here, we hypothesize that HO-1 is a key modulator of genes associated with stemness and metastasis during the crosstalk of PCa cells with bone progenitors.We used an indirect coculture system of PC3 cells (PCa) grown with MC3T3 cells (bone progenitors) to model PCa-bone crosstalk. PC3 cells were pretreated or not with hemin, a specific pharmacological inducer of HO-1. We performed RNAseq analyses and assessed the transcriptome of PC3 cells focusing on genes associated with stemness (CD44, CD133 and pluripotency markers), metastasis and a stemlike signature previously identified by our group (ADAM15, BCL2L1, LTBR, MBNL2, SPINT1).PC3 cocultured with MC3T3 displayed upregulation of PCSC and pluripotency markers, as well as BCL2L1 and LTBR, when compared with PC3 cells cultured alone. Interestingly, when pre-treating PC3 cells with hemin prior to the coculture, cells displayed an impaired upregulation of these genes, including PCSC marker CD44, pointing out to the protective effect of HO-1 induction towards the pro-stemness effect triggered by the coculture.We extended our analysis using PCa patients’ survival and transcriptomic publicly available data (TCGA-PRAD (n=565), SU2C-PRAD (n=444), FHCRC-PRAD (n=176)). Results showcased that expression of CD44 not only was higher in bone metastases vs. primary PCa tumors, but was also among the subgroup of genes associated with significant changes in patients’ survival.Altogether, HO-1 expression modulates stemness and metastasis related genes in PCa cells, promoting a more differentiated state, counteracting the pro-stemness effect linked to the communication with bone progenitors. This supports the antitumoral role of HO-1 in PCa and highlights CD44 as a relevant candidate for further studies.