Sargent, J. K. | Search bioRxiv

bioRxiv2026

Genetically distinct microenvironment determines cancer survival and response to therapy in mice

Genetic uniqueness of the tumor microenvironment significantly influences cancer growth, survival, and response to therapy, independent of the cancer cells intrinsic properties or the adaptive immune system. Using genetically distinct Rag1-/- mouse models, this study shows that different strains exhibit varied tumor growth kinetics and survival outcomes when xenografted with identical leukemic and solid tumor cell lines. This study further highlights the critical role of the myeloid immune compartment and shows that disrupting both lymphoid and myeloid systems alters cancer progression. These results also reveal that the tumor microenvironment can permanently alter cancer cell phenotypes and significantly affect chemotherapy efficacy, as seen with Cisplatins varying effects across strains. These findings underscore the importance of considering genetic background in preclinical cancer models, suggesting that reliance upon a single mouse strain may lead to incomplete conclusions about cancer biology and treatment efficacy. SUMMARY STATEMENTPre-clinical xenograft mammalian models are used to study human diseases. Here we report that the genetic uniqueness of the tumor microenvironment, independent of the immune system, can determine the fate of cancer progression, survival, and therapy response.

cancer biology↗

bioRxiv2024

Methods to study xenografted human cancer in genetically diverse mice

Xenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancer in vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell line in vivo to reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a "difficult to xenograft" PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.

cancer biology↗