1. Phenotype screens of murine pancreatic cancer identify a Tgf-[alpha]-Ccl2-paxillin axis driving human-like neural invasion
- Author
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Wang, Xiaobo, Istvanffy, Rouzanna, Ye, Linhan, Teller, Steffen, Laschinger, Melanie, Diakopoulos, Kalliope N., Gorgulu, Kivanc, Li, Qiaolin, Ren, Lei, Jager, Carsten, Steiger, Katja, Muckenhuber, Alexander, Vilne, Baiba, Cifcibasi, Kaan, Reyes, Carmen Mota, Yurteri, Ummugulsum, Kiessler, Maximilian, Gurcinar, Ibrahim Halil, Sugden, Maya, Yildizhan, Saliha Elif, Sezerman, Osman Ugur, Cilingir, Sumeyye, Suyen, Guldal, Reichert, Maximilian, Schmid, Roland M., Barthel, Stefanie, Oellinger, Rupert, Kruger, Achim, Rad, Roland, Saur, Dieter, Algul, Hana, Friess, Helmut, Lesina, Marina, Ceyhan, Guralp Onur, and Demir, Ihsan Ekin
- Subjects
Neurons -- Analysis -- Genetic aspects ,Tumor proteins -- Development and progression -- Prognosis -- Genetic aspects ,Genetic engineering -- Genetic aspects -- Analysis ,Transforming growth factors -- Genetic aspects -- Analysis ,Genetically modified organisms -- Analysis -- Genetic aspects ,Pancreatic cancer -- Genetic aspects -- Development and progression -- Prognosis ,Health care industry - Abstract
Solid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor [alpha] (TGF-[alpha]) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-[alpha] upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-[alpha]-expression constituted strong prognostic factors. Therefore, we believe that the TGF- [alpha]-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC., Introduction Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-associated death worldwide and is projected to become the second by 2030 (1). Remarkable progress has been made [...]
- Published
- 2023
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