Abstract This study investigates how pancreatic cancer cells utilize LAMA5 to build an autonomous niche that promotes survival and metastasis, revealing novel therapeutic vulnerabilities. A stiff and fibrotic extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDAC). This dense microenvironment impedes drug penetration, contributing to pronounced therapeutic refractoriness and poor patient survival. While stromal cells are classically regarded as the primary source of ECM, recent evidence suggests that tumor cells themselves can generate matrix components, establishing an autonomous survival niche. Laminin-α5 (LAMA5), a key basement membrane protein, regulates epithelial adhesion, polarity, and migration, yet its tumor-intrinsic role in PDAC remains unexplored. Our comprehensive interrogation of bulk, single-cell RNA sequencing, and spatial transcriptomics datasets revealed selective enrichment of LAMA5 within malignant epithelial cells rather than the stromal compartment. In a clinical context, immunohistochemistry of human PDAC patient samples showed marked upregulation compared with adjacent normal pancreas, and further elevation in metastatic cell clusters in the liver. Next, in murine PDAC progression models (KC: Kras; PdxCre and KPC: Kras; p53; PdxCre), the ductal cell-derived contribution of LAMA5 increased progressively with disease severity, surpassing stromal expression. KPC-derived organoids similarly exhibited enhanced luminal LAMA5 expression compared with normal ducts, as confirmed by multiplex immunofluorescence, indicating robust secretion by tumor ductal epithelium. Long-term LAMA5 depletion in primary and metastatic human PDAC cell lines impaired proliferation, cell adhesion, anchorage-independent growth, and survival under non-adherent conditions, indicating a role in protecting against anoikis (apoptosis due to loss of attachment to ECM). Interestingly, supplementation with extracellular LAMA5 restored these phenotypes, establishing LAMA5 as a key mediator of adhesion-dependent survival. Tumor cells also exhibited elevated expression of LAMA5-binding receptors ITGA6, ITGB4, and BCAM, supporting an autocrine survival loop that reinforces epithelial adhesion and stress tolerance. To uncover therapeutic vulnerabilities, connectivity mapping through the iLINCS platform identified an FDA-approved compound, Lomustine, which reduced LAMA5 expression and markedly inhibited the growth of mouse and human PDAC organoids. Our findings collectively show that PDAC cells secrete LAMA5 to build a self-made matrix microenvironment that supports survival, adhesion, and metastatic persistence. Tumor-intrinsic LAMA5 redefines the tumor-stroma paradigm, enabling microenvironmental autonomy and anoikis-resistance, and highlights potential targets for intervention in PDAC. Citation Format: Annant Bir Kaur, Nivedeta Krishna Kumar, Pratima Raut, Kirtana Arikath, Venkatesh Varadharaj, Zahraa Wajih Alsafwani, Jesse Cox, Poompozhil Mathivanan, Surindar K. Batra, Moorthy P Ponnusamy, . Self-made matrix: Tumor-derived Laminin-α5 supports pancreatic cancer cell survival and metastatic persistence abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7484.
Kaur et al. (Fri,) studied this question.