Spectrin SPTAN1 loss triggers genome instability and tumor growth in bladder cancer

Spectrin alphaII (SPTAN1) is a cytoskeletal protein which plays important roles in actin filament organization and chromosome segregation. Alterations in spectrin network was found to influence cell division and enhance tumor progression. By analyzing cancer genomics data from TCGA databank, silent mutations in spectrin gene SPTAN1 and its down-regulation were frequently detected in patients with muscle invasive bladder cancer (MIBC), the most aggressive cancer type of bladder cancer. To investigate the possible role of spectrin alphaII loss in MIBC development, we established stable MB49 cell clones (SPTAN1-KD) which constitutively express SPTAN1-specific shRNAs, leading to down-regulation of SPTAN1 expression. Multinucleated cells with micronuclei were found in SPTAN1-KD cells which were associated with strong staining of gamma H 2AX and pCHK2, suggesting DNA damage and genome instability triggered by SPTAN1 loss. Interestingly, these cells can escape the genome crisis-induced cell death by down-regulating the cGAS-STING pathways, a mechanism frequently found in metastatic cancer cells with genome instability. Cell proliferation assay by MTT assay revealed enhanced growth rate in SPTAN1-KD cells as compared to control cells transfected with pLKO empty vector or the parental cells. Xenografted tumor model also confirmed higher tumor growth rate in lesions formed by SPTAN1-KD cells Transcriptome analysis indicated up-regulation of several pathways involved in T cell exhaustion, lipid metabolism and ECM remodeling in SPTAN1-KD cells, which associated with down-regulation of pathways related to immune surveillance. Our study therefore suggests that SPTAN loss functions as a driving force to promote cancer progression by inducing genome instability and cell proliferation. SPTAN loss can also enhance cancer survival by triggering immune editing through transcriptional reprograming.