Mandell, J. | Search bioRxiv

bioRxiv2026

Stepwise Evolution and Epistatic Interaction of Driver Mutations from Endometrial Hyperplasia to Carcinoma

To characterize early oncogenesis, pathologically identified pre-cancerous tissue can be analyzed for the presence of cancer drivers. Here, we argue that in such studies, analyses of the driver status of variants, of the association between step-specific prevalence and progression through tumorigenesis, and of driver co-occurrence and mutual exclusivity should be accompanied by estimates of inherent mutation rate of variants and presented within an evolutionary framework of selective epistasis. To illustrate this point, we examine the transition of endometrial tissue from atypical hyperplasia to carcinoma. We apply a step-specific analysis, demonstrating that the strength of selection on somatic driver mutations promoting cell division and survival differs between hyperplasia to carcinoma. We demonstrate that mutations of PTEN, which are highly prevalent in carcinomas and have been argued to exert substantial driver effects, exhibit an even larger effect of increasing cellular division and survival within developing hyperplasias. A determination of cooccurrence or mutual exclusivity may be a product of genes sharing or differing in underlying sources of mutation, as opposed to a product of biological interaction and selection. By accounting for tumor-specific mutational processes that influence co-occurrence, we calculate epistatic selective intensities between pairs of drivers. Mutations of KRAS and FGFR2 are often mutually exclusive and were indeed found to exhibit significant antagonistic selective epistasis. However, mutations of PIK3CA and PIK3R1, which also have been identified as showing mutual exclusivity, do not demonstrate significant antagonistic selective epistasis. Thus, evidence of mutually exclusivity is insufficient to determine epistasis. Accordingly, the application of quantitative approaches that distinctly analyze mutation and selection on cancer variants has the potential to substantially illuminate the trajectory of tumorigenesis and cancer progression.

Cancer Biology↗

bioRxiv2025

S1PR3 mediates glial stimulated tumor invasion in response to interstitial fluid flow

Cellular invasion is a primary challenge to complete resection and treatment of glioblastoma, the most aggressive and deadly primary brain tumor. The brain tumor microenvironment actively stimulates glioma invasion through a multitude of cellular, chemical, and biophysical cues. We and others have shown elevated interstitial fluid flow at the tumor border is one such biophysical cue that directly stimulates invasion through tumor-intrinsic signaling and, in other tumor types, priming of cancer-associated stromal cells. It is currently unclear if interstitial flow similarly primes neuroglial cells to promote glioma cell dissemination and can be targeted for therapeutic purposes. Here, we show elevated interstitial flow upregulates expression of sphingosine-1-phosphate receptor 3 (S1PR3) in glial astrocytes and microglia, which drives glioma cell invasion via chemotaxis. Flow-induced expression of glial S1PR3 is tumor-independent and displays a biphasic relationship to fluid shear stress magnitude in vitro and flow rate in vivo. Inhibition of glial S1PR3 in a tissue engineered culture model and orthotopic mouse model abrogates flow-stimulated invasion, demonstrating a tumor-extrinsic approach to limiting glioblastoma progression. Given prior evidence of a pro-inflammatory role for glial S1PR3, identification of S1PR3 as a disease-agnostic marker of flow-stimulated glia may also have therapeutic implications across myriad neuropathologies.

cancer biology↗