Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and we identified and experimentally validated several oncogene-miRNA-tumor suppressor axes. According to our analyses, we found SPARC as an APA-regulated oncogene in cancer-associated fibroblasts in NSCLC. Knockdown of SPARC attenuates lung cancer cell invasion and metastasis. Moreover, we found high SPARC expression associated with resistance to several drugs except cisplatin. NSCLC patients with high SPARC expression could benefit more compared to low-SPARC-expression patients with cisplatin treatment. Overall, our comprehensive analysis of cell-specific APA events shed light on the regulatory mechanism of cell-specific oncogenes and provided opportunities for combination of APA-regulated therapeutic target and cell-specific therapy development.© 2023 The Authors.