Wismer, H. | bioRxiv Science

bioRxiv2025

Differential Assembly of Mouse and Human Tumor Microenvironments

Mouse models are frequently used to develop treatments for human cancer. Yet, we lack a comprehensive understanding of the comparative organization of mouse and human tumor microenvironments (mu/huTMEs). Through immunoprofiling of commonly used mouse models, we found that the immune composition of most muTMEs resemble poorly infiltrated human tumors extensively biased toward high macrophages densities. Relatedly, we discover species-specific biases of chemokine expression networks, factors which drive TMEs assembly. Further, assessing coarse cellular networks, we find conserved correlations between some immune cell frequencies, while other relationships only appear conserved in the huTMEs matching muTME profiles. Despite this variable alignment, we define robust cell type-specific gene expression programs conserved in TMEs across species and cohorts and identify ones that are coordinated between cell populations in both species. Together, we isolate and offer methods to study the multiple areas of hazard and opportunities for using mice to model human cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/661217v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@22bcf7org.highwire.dtl.DTLVardef@a410b7org.highwire.dtl.DTLVardef@1455eb5org.highwire.dtl.DTLVardef@14cc6f5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRASG12C (G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAPS127A mutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/615226v3_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1b22ef5org.highwire.dtl.DTLVardef@128ed3corg.highwire.dtl.DTLVardef@1ef1e89org.highwire.dtl.DTLVardef@1bdc0a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗