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Preprint WatchStrongOctober 3rd, 2026

Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.

Hayashi, Y.; Elias, R.; Douglass, E.; Yamamoto, A.; Schuler, M.; Feng, M.; Batourina, E. Y.; Geller, A. E.; Choi, W.; Colocho, G.; Arbuiso, A.; Jin, S.; Aragaki, A. K.; Ruland, C.; Rapiey, S.; Hoffman-Censits, J.; Kates, M.; Patel, S.; Singla, N.; Smith, A.; Russell, S.; Li, H.; Warrick, J. I.; Baraban, E.; Allenspach, K.; Mendelsohn, C. L.; Matoso, A.; Hahn, N. M.; McConkey, D. J.; Johnson, B. A.

PD-L1 is highly expressed in sarcomatoid urothelial carcinoma (combined positive score above 50 in 20 of 38 human cases) and anti-PD-1 checkpoint blockade significantly inhibits tumour growth in a matched murine sarcomatoid model, supporting PD-1 blockade as a therapeutic strategy in this variant histology.

Strong contradiction

6 prior failures

Three or more documented clinical failures match this mechanism, or a Phase 3 efficacy failure is on record.

This preprint reports that 20 of 38 human sarcomatoid urothelial carcinomas carried a PD-L1 combined positive score above 50, and that an anti-PD-1 antibody significantly inhibited growth of the BBN966 murine sarcomatoid model, with a mixed response in the hybrid BBN964 model. The flag is raised because Claidex holds six PDCD1 failures, four of them coded as efficacy failures. KEYNOTE-991 and KEYNOTE-641 both stopped for futility in metastatic prostate cancer (pembrolizumab-enzalutamide-pdcd1-mhspc-keynote-991-phase3-efficacy-failure, pembrolizumab-enzalutamide-pdcd1-mcrpc-keynote-641-phase3-efficacy-failure), KEYNOTE-630 stopped for futility in adjuvant cutaneous squamous cell carcinoma despite high tumour mutational burden (pembrolizumab-pdcd1-adjuvant-locally-advanced-cscc-keynote-630-phase3-efficacy-failure), and camrelizumab missed in first-line cervical carcinoma (camrelizumab-apatinib-pdcd1-first-line-cervical-cancer-phase2-efficacy-failure), alongside two strategic terminations in head and neck and post-platinum lung cancer (pds0101-pembrolizumab-pdcd1-hpv16-head-neck-versatile-003-phase3-strategic-reprioritization, js207-pdcd1-vegfa-post-platinum-nsclc-phase2-strategic-reprioritization). Two qualifications belong on this flag. None of the recorded failures is in urothelial carcinoma, where PD-1 blockade is already established, so the preprint does not contradict the Claidex record. And high PD-L1 expression is the variable that has repeatedly failed to predict benefit in the recorded trials, which is the specific inference this preclinical result invites. The transferable caution is that a tumour-growth effect in one syngeneic model plus a PD-L1 immunohistochemistry distribution is a weaker basis for an indication decision than the number of PD-1 programmes already recorded as stopped would suggest.

Abstract excerpt

Patients with majority variant subtype histology including sarcomatoid urothelial carcinoma (SUC) have poor outcomes and limited treatment options, and there are few preclinical resources to investigate rare histologic subtypes. We developed three novel variant subtype histology bladder cancer (BC) cell lines by finding that basal BC tumor cells derived from mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were initially not competent to grow in immune competent mice, but then acquired tumorigenicity following passaging (recycling) in mice lacking mature B and T cells. Three genitourinary oncology pathologists identified BBN966 as SUC, BBN964 as a hybrid between SUC and squamous, and BBN975 as squamous, and each had unique growth characteristics. Using a publicly available dataset and our spatial transcriptomics analysis of a cohort of human tumors with mixed SUC and UC as comparators, we found that consistent with human SUC, BBN966 lack expression of basal and luminal genes. Consistent with human SUC and spatial transcriptomics analysis of canine SUC, BBN966 had the highest epithelial to mesenchymal transition (EMT) upregulation, and all three recycled tumor cells had increased EMT pathway expression in recycled tumor cells. Moreover, increased expression of genes upregulated in all three recycled tumor cells associated with worse overall survival in patients with muscle invasive UC. Similar to human SUC, BBN966 tumors had higher proportion of M2 macrophage gene expression. Finally, we found in the largest cohort of PD-L1 IHC to date that 20 of 38 (52.6%) human SUC had CPS > 50, which was driven mostly by tumor proportion score. Consistent with this, we found anti-PD1 immune checkpoint inhibitor (ICI) significantly inhibited BBN966 tumor growth, while the hybrid BBN964 tumors had mixed response to ICI. Thus, the murine BBN966 tumors exhibited similarities to human SUC, and can be used to examine novel therapies for translation into future SUC clinical studies.

Matching Claidex post-mortems

6 of 6 indexed

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.