Lord, S. R. | bioRxiv Science

bioRxiv2025

Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS-chemokine-myeloid axis

Chromosomal instability (CIN), a characteristic feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and therapy resistance, presenting an intractable problem in cancer treatment. CIN leads to constitutive stimulation of the innate immune cGAS-STING pathway, which has been typically linked to anti-tumor immunity. However, despite the high CIN burden in EAC, the cGAS- STING pathway remains largely intact. To address this paradox, we developed novel esophageal cancer models, including a CIN-isogenic model, discovering myeloid-attracting chemokines - with the chemokine CXCL8 (IL-8) as a prominent hit - as conserved CIN-driven targets in EAC. Using high-resolution multiplexed immunofluorescence microscopy, we quantified the extent of ongoing cGAS-activating CIN in human EAC tumors by measuring cGAS-positive micronuclei in tumor cells, validated by orthogonal whole-genome sequencing-based CIN metrics. By coupling in situ CIN assessment with single-nucleus RNA sequencing and multiplex immunophenotypic profiling, we found tumor cell-intrinsic innate immune activation and intratumoral myeloid cell inflammation as phenotypic consequences of CIN in EAC. Additionally, we identified increased tumor cell-intrinsic CXCL8 expression in CINhigh EAC, accounting for the inflammatory tumor microenvironment. Using a novel signature of CIN, termed CINMN, which captures ongoing CIN-associated gene expression, we confirm poor patient outcomes in CINhigh tumors with signs of aberrantly rewired cGAS-STING pathway signaling. Together, our findings help explain the counterintuitive maintenance and expression of cGAS-STING pathway components in aggressive, CINhigh tumors and emphasize the need to understand the contribution of CIN to the shaping of a pro-tumor immune landscape. Therapeutic strategies aimed at disrupting the cGAS-driven inflammation axis may be instrumental in improving patient outcomes in this aggressive cancer.

cancer biology↗

bioRxiv2018

Exposure to unpredictable trips and slips while walking can improve balance recovery responses with minimum predictive gait alterations

INTRODUCTIONThis study aimed to determine if repeated exposure to unpredictable trips and slips while walking can improve balance recovery responses when predictive gait alterations (e.g. slowing down) are minimised.\n\nMETHODSTen young adults walked on a 10-m walkway that induced slips and trips in fixed and random locations. Participants were exposed to a total of 12 slips, 12 trips and 6 non-perturbed walks in three conditions: 1) right leg fixed location, 2) left leg fixed location and 3) random leg and location. Kinematics during non-perturbed walks and previous and recovery steps were analysed.\n\nRESULTSThroughout the three conditions, participants walked with similar gait speed, step length and cadence(p>0.05). Participants extrapolated centre of mass (XCoM) was anteriorly shifted immediately before slips at the fixed location (p<0.01), but this predictive gait alteration did not transfer to random perturbation locations. Improved balance recovery from trips in the random location was indicated by increased margin of stability and step length during recovery steps (p<0.05). Changes in balance recovery from slips in the random location was shown by reduced backward XCoM displacement and reduced slip speed during recovery steps (p<0.05).\n\nCONCLUSIONSEven in the absence of most predictive gait alterations, balance recovery responses to trips and slips were improved through exposure to repeated unpredictable perturbations. A common predictive gait alteration to lean forward immediately before a slip was not useful when the perturbation location was unpredictable. Training balance recovery with unpredictable perturbations may be beneficial to fall avoidance in everyday life.

physiology↗