Jensen-Smith, H. | Search bioRxiv

bioRxiv2025

Spatial Proteomics of the Normal Breast Collagen Stroma: Links to BI-RADS Categories and Body Mass Index

Collagen breast stroma is the basis of increased breast density and a well-established breast cancer risk factor, yet proteomic regulation of normal breast stroma remains poorly defined. This study reports spatial regulation of the collagen proteome in normal breast tissue sections annotated by clinical characteristics. Normal breast samples from the Susan G. Komen tissue bank included data on genetic ancestry (n=40 total; n=20 African ancestry; n=20 European ancestry), body-mass-index (BMI), age, and mammogram density by the Breast Imaging Reporting and Data System (BI-RADS). Multiplexed cell marker staining showed CD44 and COL1A1 markers modulated with BMI. Collagen fiber widths by second harmonic generation (SHG) showed potential contrasts in BMI categories by genetic ancestry. Targeted extracellular matrix proteomics mass spectrometry imaging showed collagen alpha-1(I) chain domain proteome was spatially heterogenous across the normal breast microenvironment with site specific post-translational modification of proline hydroxylation. Signatures computationally extracted from breast stroma reported that 47 collagen peptides distinguished BI-RADS categories (area under the receiver operating curve>0.7; p-value>0.05). Proteomic alterations were found between overweight to obese categories with strong positive associations to BMI by multivariate analysis. This study provides the first spatial analysis of the collagen proteome in normal breast within contexts of cellular markers and clinical characteristics.

cancer biology↗

bioRxiv2022

Androgen-mediated TGFβ expression suppresses anti-tumor neutrophil response in bone metastatic prostate cancer

Prostate Cancer (PCa) bone metastases are associated with spinal cord compression, fracture, bone pain and death. Despite advances in the medical therapy for localized disease, metastatic disease is incurable and osseous progression is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that tumor bone neutrophils are tumoricidal to PCa but lose their cytotoxic potential as the tumor progresses. However, there have been no studies to date to clinically define and characterize neutrophils throughout the prostate cancer disease spectrum to determine their biomarker potential. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identify that PCa progression dictates PMN properties, including viability, cell surface markers and gene expression. However, the majority of PMNs elicited an anti-tumor response ex vivo demonstrating that PMN cytotoxicity is cell autonomous and independent of PCa disease stage. In fact, we identify a novel role for androgen regulation, i.e., androgen deprivation therapy (ADT), in suppressing PMN cytotoxicity via altered transforming growth factor beta receptor I (T{beta}RI). Using preclinical models, we found that high dose testosterone/bipolar androgen therapy (BAT) and genetic or pharmacologic T{beta}RI inhibition combined with standard ADT rescued the androgen-associated suppression and restored PMN anti-tumor immune response. This combination provided a therapeutic strategy more impactful than ADT alone, in bone metastatic prostate cancer (BM-PCa). These studies: 1) highlight a necessity for both molecular and functional characterization of PMNs per cancer type and 2) reveals the ability to program PMN immune response for successful targeting of BM-PCa.

cancer biology↗