Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.

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 α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α 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-α-expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

Regulatory T Cells in Pancreatic Cancer: Of Mice and Men.

Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of αSMA+ myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8+ cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.

Schwann Cells in Peripheral Cancers: Bystanders or Promoters?

The tumor microenvironment is subject to intense investigation in terms of its influence on tumorigenesis. Despite the fact that Schwann cells are cancer cells' early interaction partners, investigations on tumor progression and the molecular drivers of carcinogenesis do not place enough emphasis on them. Recent studies have shown that malignant cells and nerves interact on several levels during early carcinogenesis. For instance, the emergence of nerves in cancer, known as cancer neo-neurogenesis, is one important mechanism that contributes to cancer progression. Recent studies on Schwann cells brought the investigation of tumor-nerve interactions to a whole new level. Schwann cells make up the majority of glial cells in the peripheral nervous system, are outstandingly plastic cells, and serve a variety of roles in most organs. All these properties make Schwann cells excellent potential targets for tumor cells to exploit and turn them into promoters of carcinogenesis. In the present review, the distinctive features of Schwann cell-tumor cell interactions and the implications of this interaction on the tumor microenvironment are outlined. Further, this study points out the neglected aspects of Schwann cells in the tumor microenvironment and provides a potential new avenue for future research.