Hieromnimon, H. | bioRxiv Science

bioRxiv2024

Generative Adversarial Networks Accurately Reconstruct Pan-Cancer Histology from Pathologic, Genomic, and Radiographic Latent Features

Artificial intelligence models have been increasingly used in the analysis of tumor histology to perform tasks ranging from routine classification to identification of novel molecular features. These approaches distill cancer histologic images into high-level features which are used in predictions, but understanding the biologic meaning of such features remains challenging. We present and validate a custom generative adversarial network - HistoXGAN - capable of reconstructing representative histology using feature vectors produced by common feature extractors. We evaluate HistoXGAN across 29 cancer subtypes and demonstrate that reconstructed images retain information regarding tumor grade, histologic subtype, and gene expression patterns. We leverage HistoXGAN to illustrate the underlying histologic features for deep learning models for actionable mutations, identify model reliance on histologic batch effect in predictions, and demonstrate accurate reconstruction of tumor histology from radiographic imaging for a virtual biopsy.

cancer biology↗

bioRxiv2023

Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis

PurposePTEN loss-of-function/PI3K pathway hyperactivation occurs in [~]50% of metastatic, castrate-resistant prostate cancer patients, resulting in poor therapeutic outcomes and resistance to immune checkpoint inhibitors across multiple malignancies. Our prior studies in prostate-specific PTEN/p53-deleted genetically engineered mice (Pb-Cre;PTENfl/flTrp53fl/fl GEM) with aggressive-variant prostate cancer (AVPC) demonstrated feedback Wnt/{beta}-catenin signaling activation in 40% mice resistant to androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody (aPD-1) combination, resulting in restoration of lactate cross-talk between tumor-cells and tumor-associated macrophages (TAM), histone lactylation (H3K18lac) and phagocytic suppression within TAM. Here, we targeted immunometabolic mechanism(s) of resistance to ADT/PI3Ki/aPD-1 combination, with the goal of durable tumor control in PTEN/p53-deficient PC. Experimental designPb-Cre;PTENfl/flTrp53fl/fl GEM were treated with either ADT (degarelix), PI3Ki (copanlisib), aPD-1, MEK inhibitor (trametinib) or Porcupine inhibitor (LGK 974) as single agents or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo co-culture mechanistic studies were performed on prostate tumors or established GEM-derived cell lines. ResultsWe tested whether Wnt/{beta}-catenin pathway inhibition with LGK 974 addition to degarelix/copanlisib/aPD-1 therapy enhances tumor control in GEM, and observed de novo resistance due to feedback activation of MEK signaling. Based on our observation that degarelix/aPD-1 treatment resulted in partial inhibition of MEK signaling, we substituted trametinib for degarelix/aPD-1 treatment, and observed a durable tumor growth control of PI3Ki/MEKi/PORCNi in 100% mice via H3K18lac suppression and complete TAM activation within TME. ConclusionsAbrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials. STATEMENT OF TRANSLATIONAL RELEVANCEPTEN loss-of-function occurs in [~]50% of mCRPC patients, and associated with poor prognosis, and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies have demonstrated that ADT/PI3Ki/PD-1 triplet combination therapy controls PTEN/p53-deficient PC in 60% of mice via enhancement of TAM phagocytosis. Here, we discovered that resistance to ADT/PI3K/PD-1 therapy occurred via restoration of lactate production via feedback Wnt/MEK signaling following treatment with PI3Ki, resulting in inhibition of TAM phagocytosis. Critically, co-targeting of PI3K/MEK/Wnt signaling pathways using an intermittent dosing schedule of corresponding targeted agents resulted in complete tumor control and significantly prolonged survival without significant long-term toxicity. Collectively, our findings provide "proof-of-concept" that targeting lactate as a macrophage phagocytic checkpoint controls growth of murine PTEN/p53-deficient PC and warrant further investigation in AVPC clinical trials.

cancer biology↗