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Preprint WatchModerateOctober 13th, 2026

CXCL-CXCR2 signaling drives cancer-endothelium interactions in SCLC metastatic seeding

Yang, Z.; Xu, A.; Hughes, N.; Peng, C.-W.; Visani, A.; Narayanan, S. P.; Ng, X. W.; Guppy, I.; Roberts, C.; You, Y.; Winslow, M. M.; Piston, D. W.; Park, J.; Lyu, Z.; Chen, F.; Ding, L.; Tang, R.

Endothelial-cell-derived CXCL chemokines activate cancer-intrinsic CXCR2-RAC1 signalling to drive RAC1-dependent F-actin assembly, SCLC motility and liver metastatic seeding, and pharmacologic CXCR2 or RAC1 inhibition suppresses migration and prevents liver metastasis in model systems.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The Claidex CXCR2 record holds a single human efficacy failure, ladarixin in recent-onset type 1 diabetes, stopped for protocol-defined futility after failing to preserve C-peptide at month 6 and at every later timepoint (ladarixin-cxcr2-recent-onset-type-1-diabetes-gladiator-phase2-efficacy-failure). This preprint makes a CXCR2 claim in an unrelated setting, small cell lung cancer liver metastasis, where endothelial CXCL chemokines activate a cancer-cell-intrinsic CXCR2-RAC1 motility circuit and pharmacologic CXCR2 inhibition prevents metastatic seeding in model systems. The flag is raised because the shared target already carries a documented efficacy failure in humans, not because the two findings conflict. What transfers is a caution about context dependence: the ladarixin programme assumed CXCR2 blockade would protect beta cells by limiting neutrophil and monocyte trafficking and it did not, whereas the preprint locates the actionable CXCR2 pool inside the tumour cell rather than on recruited leukocytes. Any oncology programme built on this result should state which CXCR2 pool it intends to block, and should not read preclinical metastasis prevention as evidence that systemic CXCR2 inhibition behaves predictably in patients, since the one human efficacy test on file was negative.

Abstract excerpt

Small cell lung cancer (SCLC) is a highly metastatic malignancy with tropism to the liver, yet the signals that enable organ-specific metastatic colonization remain largely undefined. During metastasis, disseminated cancer cells first encounter endothelial cells (ECs) at the vascular-tissue interface, positioning cancer-endothelium crosstalk as a key determinant of metastatic success. Defining the signaling pathways underlying this reciprocal communication may uncover actionable vulnerabilities for preventing and treating this lethal disease. Here, we uncover an EC-derived CXCL chemokine program that activates cancer-intrinsic CXCR2-RAC1 signaling as a critical mediator of SCLC liver metastasis. By integrating in vitro and in vivo models, we show that SCLC cells induce robust CXCL chemokine expression from liver ECs, which in turn enhances SCLC migration and reinforces cancer cell-EC interactions. We applied highly quantitative metastatic colony barcode sequencing coupled with individual gene inactivation to demonstrate that CXCR2 is essential for SCLC migration and liver metastatic seeding. Mechanistically, CXCL-CXCR2 signaling activates RAC1-dependent F-actin assembling to drive SCLC motility during CXCL-induced metastatic seeding. Pharmacologic inhibition of CXCR2 or RAC1 suppresses SCLC migration and prevents SCLC liver metastasis. Together, our research defined a chemokine-driven signaling circuit that governs cancer-endothelium communication during the metastatic cascade and nominate the CXCL-CXCR2-RAC1 axis as a promising therapeutic vulnerability for preventing and treating metastatic SCLC.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.