Michael Xu

The Duffy-null phenotype is associated with fewer circulating blood neutrophils. This phenomenon, termed Duffy-null-associated neutrophil count (DANC), is common among individuals of African and Middle Eastern ancestry. Despite growing evidence that DANC does not increase the risk of infectious complications, oncology treatment protocols often rely on standardised absolute neutrophil count (ANC) thresholds to guide chemotherapy dosing and clinical trial candidacy. This reliance risks inappropriate dose reductions or treatment delays in patients with DANC. We present a patient with DANC and high-volume metastatic hormone-sensitive prostate cancer in whom lower neutrophil counts, found to be due to DANC, delayed initiation of chemotherapy and led to the use of granulocyte-colony stimulating factor (G-CSF). This case highlights the dilemma that DANC may lead clinicians to delay chemotherapy and/or use G-CSF when neither may be needed. Future clinical studies are needed to develop DANC-specific thresholds for standard dose chemotherapy and G-CSF support.

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Supplementary Figure S2. sPOM121 is associated with transcriptionally active chromatin.

Supplementary Figure S7. sPOM121 decreases tumor infiltrating CD8+ T lymphocytes and confers poor response to anti-PD-1 therapy.

The roles of nucleoplasm-residing nucleoporins (NUP) in solid tumors, including prostate cancer, remain unknown. In this study, we reveal the clinical significance and mechanistic role of the off-pore NUP, soluble POM121 (sPOM121), as a crucial transcriptional regulator that enhances the aggressiveness of metastatic prostate cancer. Using orthogonal methodologies in human samples, sPOM121 was identified as the predominantly expressed nucleoplasmic NUP in prostate cancer. Unbiased proteomic and epigenomic studies demonstrate that sPOM121, through its C-terminus, interacts with the chromatin remodeler SMARCA5 at gene promoter sites and localizes at nuclear condensates, reprogramming gene expression. Indeed, sPOM121 regulates a distinct oncogenic gene network, including β-catenin, leading to prostate cancer progression and immune evasion. Importantly, targeting the sPOM121/β-catenin axis in patient-derived preclinical and syngeneic mouse models halts prostate cancer aggressiveness and enhances antitumor immunity. Taken together, these findings reveal previously unknown actionable reprogramming functions of off-pore NUPs in solid tumors.Significance:This study uncovers how oncogenic signaling programs are transcriptionally heightened by the NUP sPOM121 in metastatic prostate cancer. Localization of sPOM121 at active transcriptional nuclear condensates propels disease progression and immune evasion, offering novel anticancer therapeutic opportunities.

Supplementary Table S2 from Off-pore Nucleoporin sPOM121 Transcriptionally Propels β-Catenin–driven Tumor Progression and Immune Escape in Prostate Cancer

Supplementary Figure S6. The sPOM121/catenin axis contributes to prostate cancer aggressiveness.

Supplementary Figure S5. sPOM121/SMARCA5 regulate a discrete gene network.

Supplementary Figure S4. sPOM121 C-terminus regulates gene expression.