Stohr, B. A. | Search bioRxiv

bioRxiv2024

Histologic variants in bladder cancer harbor aggressive molecular features including TM4SF1 expression and a CA125+ cell state

Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for the morphological and biological differences in HV tumors. To investigate the tumor biology of HV bladder cancers, we generated a single cell RNA sequencing (scRNA- seq) atlas of nine HV tumors and three UC tumors. Our analyses revealed a tumor cell state specific to HVs that is characterized by expression of MUC16 (CA125), KRT24, and WISP2. This CA125+ cell state bears transcriptional hallmarks of epithelial-mesenchymal transition, is enriched in metastases, is predicted to be highly chemotherapy resistant, and is linked with poor survival, suggesting that this cell state plays an important role in the aggressive biology of HV tumors. Our analyses also provide novel evidence of transcriptional "mimicry" between HVs and histologically similar non-urothelial cell types. Lastly, we identified higher expression of TM4SF1, a cell surface protein associated with cancer metastasis, in HV tumor cells compared to UC tumor cells. Finally, CAR T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression- dependent manner, highlighting its potential as a therapeutic target in bladder cancer. One sentence summarySingle cell RNA sequencing of primary bladder cancers identified a CA125+ cell state specific to histologic variants that is associated with aggressive biological features and TM4SF1 as a novel therapeutic target for histologic variant subtypes of bladder cancer which can be targeted by anti- TM4SF1 CAR T cells.

cancer biology↗

bioRxiv2023

Multicolor on-chip fluorescence microscopy for real-time surgical guidance

In curative-intent cancer surgery, intraoperative fluorescence imaging of both diseased and healthy tissue can help to ensure successful removal of all gross and microscopic disease with minimal damage to neighboring critical structures, such as nerves. Current fluorescence-guided surgery (FGS) systems, however, rely on bulky and rigid optics that incur performance-limiting trade-offs between sensitivity and maneuverability. Moreover, many FGS systems are incapable of multiplexed imaging. As a result, clinical FGS is currently limited to millimeter-scale detection of a single fluorescent target. Here we present a scalable, lens-less fluorescence imaging chip, VISION, capable of sensitive and multiplexed detection within a compact form factor. Central to VISION is a novel optical frontend design combining a low-numerical-aperture fiber optic plate (LNA-FOP) and a multi-bandpass interference filter, which is affixed to a custom CMOS image sensor. The LNA-FOP acts as a planar collimator to improve resolution and compensate for the angle-sensitivity of the interference filter, enabling high-resolution and multiplexed fluorescence imaging without lenses. We show VISION is capable of detecting tumor foci of less than 100 cells at near video framerates and, as proof of principle, can simultaneously visualize both tumor and nerves in ex vivo prostate tissue.

cancer biology↗